Substituted heterocyclic compounds

ABSTRACT

The present invention relates to substituted heterocyclic compounds and substituted tetrahydroisoquinoline compounds and methods of synthesizing these compounds. The present invention also relates to pharmaceutical compositions containing substituted benzodiazepine compounds and substituted tetrahydroisoquinoline compounds and methods of treating cell proliferative disorders, such as cancer, by administering these compounds or pharmaceutical compositions to subjects in need thereof.

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.61/165,121, filed Mar. 31, 2009, and U.S. Provisional Application No.61/165,075, filed Mar. 31, 2009, the contents of each of which areincorporated herein by reference in their entireties.

BACKGROUND OF THE INVENTION

Cancer is the second leading cause of death in the United States,exceeded only by heart disease. (Cancer Facts and Figures 2004, AmericanCancer Society, Inc.). Despite recent advances in cancer diagnosis andtreatment, surgery and radiotherapy may be curative if a cancer is foundearly, but current drug therapies for metastatic disease are mostlypalliative and seldom offer a long-term cure. Even with newchemotherapies entering the market, the need continues for new drugseffective in monotherapy or in combination with existing agents as firstline therapy, and as second and third line therapies in treatment ofresistant tumors.

Cancer cells are by definition heterogeneous. For example, within asingle tissue or cell type, multiple mutational “mechanisms” may lead tothe development of cancer. As such, heterogeneity frequently existsbetween cancer cells taken from tumors of the same tissue and same typethat have originated in different individuals. Frequently observedmutational “mechanisms” associated with some cancers may differ betweenone tissue type and another (e.g., frequently observed mutational“mechanisms” leading to colon cancer may differ from frequently observed“mechanisms” leading to leukemias). It is therefore often difficult topredict whether a particular cancer will respond to a particularchemotherapeutic agent (Cancer Medicine, 5^(th) edition, Bast et al., B.C. Decker Inc., Hamilton, Ontario).

Components of cellular signal transduction pathways that regulate thegrowth and differentiation of normal cells can, when dysregulated, leadto the development of cellular proliferative disorders and cancer.Mutations in cellular signaling proteins may cause such proteins tobecome expressed or activated at inappropriate levels or atinappropriate times during the cell cycle, which in turn may lead touncontrolled cellular growth or changes in cell-cell attachmentproperties. For example, dysregulation of receptor tyrosine kinases bymutation, gene rearrangement, gene amplification, and overexpression ofboth receptor and ligand has been implicated in the development andprogression of human cancers.

RET (rearranged during transfection) receptor is a novel oncogene thatencodes the RET receptor tyrosine kinase. RET has essential roles incell survival, differentiation, proliferation and migration. Studieshave shown that RET binds to, and tyrosine phosphorylates, beta-cateninand that the interaction between RET and beta-catenin can be direct andindependent of cytoplasmic kinases, such as SRC. Data have also shownthat the beta-catenin-RET kinase pathway is a critical contributor tothe development and metastasis of human carcinomas. Oncogenic activationof RET has been shown to cause the cancer syndrome multiple endocrineneoplasia type 2 (MEN 2) and is a frequent event in various thyroidcarcinomas

Tec is a member of the non-receptor, cytoplasmic protein-kinase Tecfamily, where amino acid sequence is highly conserved among members. Techas a pleckstrin homology (PH) domain, a Tec homology (TH) domain, a Srchomology (SH)-2 domain, an SH-3 domain and a kinase domain. The PHdomain binds to membrane phospholipids, and SH-2 and SH-3 domainsmediate protein-protein interactions. Tec family kinases play key rolesin receptor signaling required for cell activation, differentiation anddevelopment.

Alterations in the activity (expression) of the Tec gene are associatedwith various disorders, diseases and other deleterious conditions. Thealtered gene expression may lead to diseases, disorders and conditionsinclude inflammatory, proliferative, hyperproliferative andimmunologically-mediated diseases. Diseases and conditions associatedwith Tec family tyrosine kinases also include cancers, for example,leukemia and lymphomas, two major cancers occurring in children in theUnited States.

Eph receptors and their ligands, the ephrins, represent a large class ofcell-cell communication molecules with well-defined developmentalfunctions. Eph/Ephrin genes are widely expressed in all adult organswith certain organ-site-specific patterns. Their role in healthy adulttissues and in human disease is still largely unknown, although diverseroles in carcinogenesis have been postulated. More recent studies haveshown that EphA8 is down-regulated in some cancer and proliferativedisorders, such as, colon cancer and glioblastomas.

The ephrin type-A receptor 8 (EphA8) gene encodes a member of the ephrinreceptor subfamily of the protein-tyrosine kinase family. EPH andEPH-related receptors have been implicated in mediating developmentalevents, particularly in the nervous system. Receptors in the EPHsubfamily typically have a single kinase domain and an extracellularregion containing a Cys-rich domain and 2 fibronectin type III repeats.The ephrin receptors are divided into 2 groups based on the similarityof their extracellular domain sequences and their affinities for bindingephrin-A and ephrin-B ligands. The protein encoded by this genefunctions as a receptor for ephrin A2, A3 and A5 and plays a role inshort-range contact-mediated axonal guidance during development of themammalian nervous system.

Accordingly, new compounds and methods for modulating RET, EphA8 and Tecgenes and treating proliferation disorders, including cancer, areneeded. The present invention addresses these needs.

SUMMARY OF THE INVENTION

The present invention provides, in part, substituted heterocycliccompounds and substituted tetrahydroisoquinoline compounds of formulaeI, Ia, Ib, II, IIa and IIb and methods of preparing the compounds offormulae I, Ia, Ib, II, IIa and IIb:

or a salt or ester thereof, wherein,

one of Z₁ and Z₂ is CR₃ the other is N;

X₂ and X₄ are independently C(O) or CH₂;

X₃ is CR_(a)R_(b);

Y is unsubstituted or substituted C₁-C₆ alkyl linker or a bond;

Z is —(CH₂)_(n)—, —CH₂—O—(CH₂)_(n)— or a bond;

m is 0, 1, 2, 3, 4;

n is 1, 2, 3, 4, 5, 6;

R₁ is unsubstituted or substituted C₅-C₁₀ aryl, unsubstituted orsubstituted heteroaryl comprising 1-4 heteroatoms selected from N, O andS, unsubstituted or substituted C₃-C₁₀ carbocycle, unsubstituted orsubstituted heterocycle comprising 1-4 heteroatoms selected from N, Oand S, C(O)R_(c) or S(O)₂R_(c);

R₃ is H, halogen, unsubstituted or substituted C₁-C₈ alkyl,unsubstituted or substituted C₅-C₁₀ aryl, unsubstituted or substitutedheteroaryl comprising 1-4 heteroatoms selected from N, O and S,unsubstituted or substituted C₃-C₁₀ carbocycle or unsubstituted orsubstituted heterocycle comprising 1-4 heteroatoms selected from N, Oand S;

each R₄ is independently hydroxyl, halogen, unsubstituted or substitutedC₁-C₆ alkyl, unsubstituted or substituted C₁-C₆ alkoxyl, amino,unsubstituted or substituted C₁-C₆ alkylamino, unsubstituted orsubstituted di-(C₁-C₆)alkylamino, unsubstituted or substituted C₅-C₁₀aryl, unsubstituted or substituted heteroaryl comprising 1-4 heteroatomsselected from N, O and S, unsubstituted or substituted C₃-C₁₀carbocycle, unsubstituted or substituted heterocycle comprising 1-4heteroatoms selected from N, O and S or any two adjacent R₄'s, togetherwith the atoms to which they are attached, form a 5- to 7-member ringoptionally comprising 1-4 optionally comprising 1-4 heteroatoms selectedfrom N, O and S;

R₅ is H, unsubstituted or substituted C₁-C₆ alkyl, unsubstituted orsubstituted C₅-C₁₀ aryl, unsubstituted or substituted heteroarylcomprising 1-4 heteroatoms selected from N, O and S, unsubstituted orsubstituted C₃-C₁₀ carbocycle or unsubstituted or substitutedheterocycle comprising 1-4 heteroatoms selected from N, O and S;

R_(a) and R_(b) are independently H, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₅-C₁₀ aryl, unsubstituted orsubstituted heteroaryl comprising 1-4 heteroatoms selected from N, O andS, unsubstituted or substituted C₃-C₁₀ carbocycle, unsubstituted orsubstituted heterocycle comprising 1-4 heteroatoms selected from N, Oand S; and

R_(c) is H, unsubstituted or substituted C₁-C₈ alkyl, unsubstituted orsubstituted C₅-C₁₀ aryl, unsubstituted or substituted heteroarylcomprising 1-4 heteroatoms selected from N, O and S, unsubstituted orsubstituted C₃-C₁₀ carbocycle or unsubstituted or substitutedheterocycle comprising 1-4 heteroatoms selected from N, O and S.

The present invention also provides pharmaceutical compositionscomprising one or more compounds of formula I, Ia, Ib, II, IIa or IIband one or more pharmaceutically acceptable carriers.

The present invention also provides methods of treating a cellproliferative disorder by administering to a subject in need thereof, atherapeutically effective amount of a compound of formula I, Ia, Ib, II,IIa or IIb, or a pharmaceutically acceptable salt, prodrug, metabolite,analog or derivative thereof, in combination with a pharmaceuticallyacceptable carrier, such that the disorder is treated.

The present invention also provides methods of treating cancer byadministering to a subject in need thereof, a therapeutically effectiveamount of a compound of formula I, Ia, Ib, II, IIa or IIb, or apharmaceutically acceptable salt, prodrug, metabolite, analog orderivative thereof, in combination with a pharmaceutically acceptablecarrier, such that the cancer is treated.

The present invention also provides methods of selectively inducing celldeath in precancerous or cancerous cells by contacting a cell with aneffective amount of a compound of formula I, Ia, Ib, II, IIa or IIb, ora pharmaceutically acceptable salt, prodrug, metabolite, analog orderivative thereof, in combination with a pharmaceutically acceptablecarrier, such that contacting the cell results in selective induction ofcell death in the precancerous or cancer cells.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. In the specification, thesingular forms also include the plural unless the context clearlydictates otherwise. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent invention, suitable methods and materials are described below.All publications, patent applications, patents and other referencesmentioned herein are incorporated by reference. The references citedherein are not admitted to be prior art to the claimed invention. In thecase of conflict, the present specification, including definitions, willcontrol. In addition, the materials, methods and examples areillustrative only and are not intended to be limiting.

Other features and advantages of the invention will be apparent from thefollowing detailed description and claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel substituted heterocyclic compounds,novel substituted tetrahydroisoquinoline compounds, synthetic methodsfor making the compounds, pharmaceutical compositions containing themand various uses of the compounds.

The present invention provides compounds of formulae I, Ia and Ib:

or a salt or ester thereof, wherein:

one of Z₁ and Z₂ is CR₃ the other is N;

X₂ and X₄ are independently C(O) or CH₂;

X₃ is CR_(a)R_(b);

Y is unsubstituted or substituted C₁-C₆ alkyl linker or a bond;

m is 0, 1, 2, 3, 4;

R₁ is unsubstituted or substituted C₅-C₁₀ aryl, unsubstituted orsubstituted heteroaryl comprising 1-4 heteroatoms selected from N, O andS, unsubstituted or substituted C₃-C₁₀ carbocycle, unsubstituted orsubstituted heterocycle comprising 1-4 heteroatoms selected from N, Oand S, C(O)R_(c) or S(O)₂R_(c);

R₃ is H, halogen, unsubstituted or substituted C₁-C₈ alkyl,unsubstituted or substituted C₅-C₁₀ aryl, unsubstituted or substitutedheteroaryl comprising 1-4 heteroatoms selected from N, O and S,unsubstituted or substituted C₃-C₁₀ carbocycle or unsubstituted orsubstituted heterocycle comprising 1-4 heteroatoms selected from N, Oand S;

each R₄ is independently hydroxyl, halogen, unsubstituted or substitutedC₁-C₆ alkyl, unsubstituted or substituted C₁-C₆ alkoxyl, amino,unsubstituted or substituted C₁-C₆ alkylamino, unsubstituted orsubstituted di-(C₁-C₆)alkylamino, unsubstituted or substituted C₅-C₁₀aryl, unsubstituted or substituted heteroaryl comprising 1-4 heteroatomsselected from N, O and S, unsubstituted or substituted C₃-C₁₀carbocycle, unsubstituted or substituted heterocycle comprising 1-4heteroatoms selected from N, O and S or any two adjacent R₄'s, togetherwith the atoms to which they are attached, form a 5- to 7-member ringoptionally comprising 1-4 optionally comprising 1-4 heteroatoms selectedfrom N, O and S;

R_(a) and R_(b) are independently H, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₅-C₁₀ aryl, unsubstituted orsubstituted heteroaryl comprising 1-4 heteroatoms selected from N, O andS, unsubstituted or substituted C₃-C₁₀ carbocycle, unsubstituted orsubstituted heterocycle comprising 1-4 heteroatoms selected from N, Oand S; and

R_(c) is H, unsubstituted or substituted C₁-C₈ alkyl, unsubstituted orsubstituted C₅-C₁₀ aryl, unsubstituted or substituted heteroarylcomprising 1-4 heteroatoms selected from N, O and S, unsubstituted orsubstituted C₃-C₁₀ carbocycle or unsubstituted or substitutedheterocycle comprising 1-4 heteroatoms selected from N, O and S.

For example, Z₁ is CR₃ where R₃ is H and Z₂ is N.

For example, Z₁ is N and Z₂ is CR₃.

For example, one of X₂ and X₄ is CH₂, and the other is C(O).

For example, X₂ and X₄ are both CH₂.

For example, X₃ is CR_(a)R_(b).

For example, R_(a) and R_(b) are both H.

For example, X₂ and X₄ are both CH₂ and X₃ is CR_(a)R_(b) where R_(a)and R_(b) are both H.

For example, one of R_(a) and R_(b) is H, and the other is unsubstitutedor substituted methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl,t-butyl, n-pentyl, s-pentyl or n-hexyl.

For example, Y is unsubstituted or substituted straight-chain orbranched C₁-C₆ alkyl linker.

For example, Y is unsubstituted or substituted methyl, ethyl, n-propyl,i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl or n-hexyl.

For example, Y is a bond.

For example, Y is —CH₂—.

For example, Y is —CH₂CH₂—.

For example, Y is —CH₂CH₂CH₂—.

For example, R₁ is unsubstituted or substituted C₅-C₁₀ aryl.

For example, R₁ is unsubstituted phenyl.

For example, R₁ is substituted phenyl.

For example, R₁ is phenyl substituted with one or more groups, each ofwhich can be the same or different, selected from hydroxyl, halogen,unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or substitutedC₁-C₆ alkoxyl, amino, unsubstituted or substituted C₁-C₆ alkylamino,unsubstituted or substituted di-(C₁-C₆)alkylamino, nitro, cyano,unsubstituted or substituted acyl, unsubstituted or substituted C₁-C₆alkylcarbonyl, unsubstituted or substituted C₁-C₆ alkoxylcarbonyl,amide, unsubstituted or substituted C₁-C₆ alkylaminocarbonyl,unsubstituted or substituted di-(C₁-C₆)alkylaminocarbonyl, unsubstitutedor substituted C₅-C₁₀ aryl, unsubstituted or substituted heteroarylcomprising 1-4 heteroatoms selected from N, O and S, unsubstituted orsubstituted C₃-C₁₀ carbocycle and unsubstituted or substitutedheterocycle comprising 1-4 heteroatoms selected from N, O and S.

For example, R₁ is phenyl substituted with one or more groups, each ofwhich can be the same or different, selected from unsubstituted C₁-C₆alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl,t-butyl, n-pentyl, s-pentyl or n-hexyl).

For example, R₁ is phenyl substituted with one or more groups, each ofwhich can be the same or different, selected from substituted C₁-C₆alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl,t-butyl, n-pentyl, s-pentyl or n-hexyl).

For example, R₁ is phenyl substituted with one or more groups, each ofwhich can be the same or different, selected from substituted C₁-C₆alkyl each of which is optionally substituted with halogen (e.g.,fluorine (e.g., the substituted alkyl is —CF₃ or —CHF₂), chlorine,bromine and iodine).

For example, R₁ is phenyl substituted with one group.

For example, R₁ is phenyl substituted with two groups.

For example, R₁ is phenyl substituted with one or more groups, each ofwhich can be the same or different, selected from trifluoromethyl andtrichloromethyl.

For example, R₁ is phenyl substituted with one or more groups, each ofwhich can be the same or different, selected from unsubstituted orsubstituted C₁-C₆ alkoxyl.

For example, R₁ is phenyl substituted with one or more methoxyl.

For example, R₁ is phenyl substituted with one or more groups, each ofwhich can be the same or different, selected from fluorine, chlorine,bromine and iodine.

For example, R₁ is naphthyl and is optionally substituted with one ormore groups, each of which can be the same or different, selected fromhydroxyl, halogen, unsubstituted or substituted C₁-C₆ alkyl,unsubstituted or substituted C₁-C₆ alkoxyl, amino, unsubstituted orsubstituted C₁-C₆ alkylamino, unsubstituted or substituteddi-(C₁-C₆)alkylamino, nitro, cyano, unsubstituted or substituted acyl,unsubstituted or substituted C₁-C₆ alkylcarbonyl, unsubstituted orsubstituted C₁-C₆ alkoxylcarbonyl, amide, unsubstituted or substitutedC₁-C₆ alkylaminocarbonyl, unsubstituted or substituteddi-(C₁-C₆)alkylaminocarbonyl, unsubstituted or substituted C₅-C₁₀ aryl,unsubstituted or substituted heteroaryl comprising 1-4 heteroatomsselected from N, O and S, unsubstituted or substituted C₃-C₁₀ carbocycleand unsubstituted or substituted heterocycle comprising 1-4 heteroatomsselected from N, O and S.

For example, R₁ is unsubstituted naphthyl.

For example, R₁ is heteroaryl selected from furanyl, pyrrolyl,thiophenyl, pyrazolyl, imidazoly, oxazolyl, isoxazolyl, triazolyl,oxadiazolyl, isoxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinolinyl,naphthyridinyl, purinyl, indolyl, deazapurinyl, indolizinyl,benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimidazolyl,benzothiophenyl, methylenedioxyphenyl, benzofuranyl, and the like, andis optionally substituted with one or more groups, each of which can bethe same or different, selected from hydroxyl, halogen, unsubstituted orsubstituted C₁-C₆ alkyl, unsubstituted or substituted C₁-C₆ alkoxyl,unsubstituted or substituted C₁-C₆ alkylthio, unsubstituted orsubstituted C₁-C₆ alkylsulfinyl, unsubstituted or substituted C₁-C₆alkylsulfonyl, amino, unsubstituted or substituted C₁-C₆ alkylamino,unsubstituted or substituted di-(C₁-C₆)alkylamino, nitro, cyano, acyl,substituted acyl, unsubstituted or substituted C₁-C₆ alkylcarbonyl,unsubstituted or substituted C₁-C₆ alkoxylcarbonyl, amide, unsubstitutedor substituted C₁-C₆ alkylaminocarbonyl, unsubstituted or substituteddi-(C₁-C₆)alkylaminocarbonyl, unsubstituted or substituted C₅-C₁₀ aryl,unsubstituted or substituted heteroaryl comprising 1-4 heteroatomsselected from N, O and S, unsubstituted or substituted C₃-C₁₀ carbocycleand unsubstituted or substituted heterocycle comprising 1-4 heteroatomsselected from N, O and S.

For example, R₁ is C₃-C₁₀ carbocycle, and is optionally substituted.

For example, R₁ is cyclopentyl or cyclohexyl, and is optionallysubstituted with one or more groups, each of which can be the same ordifferent, selected from hydroxyl, halogen, unsubstituted or substitutedC₁-C₆ alkyl, unsubstituted or substituted C₁-C₆ alkoxyl, amino,unsubstituted or substituted C₁-C₆ alkylamino, unsubstituted orsubstituted di-(C₁-C₆)alkylamino, nitro, cyano, and unsubstituted orsubstituted acyl.

For example, R₁ is a heterocycle selected from pyrrolidinyl,imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl,triazolidinyl, tetrahyrofuranyl, piperidinyl, piperazinyl andmorpholinyl, and is optionally substituted with one or more groups, eachof which can be the same or different, selected from hydroxyl, halogen,unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or substitutedC₁-C₆ alkoxyl, amino, unsubstituted or substituted C₁-C₆ alkylamino,unsubstituted or substituted di-(C₁-C₆)alkylamino, nitro, cyano, andunsubstituted or substituted acyl.

For example, R₃ is H.

For example, R₃ is fluorine, chlorine, bromine or iodine.

For example, R₃ is bromine.

For example, m is 0.

For example, m is 1 or 2.

For example, each R₄ is hydroxyl, halogen, unsubstituted or substitutedC₁-C₆ alkyl, unsubstituted or substituted C₁-C₆ alkoxyl, amino,unsubstituted or substituted C₁-C₆ alkylamino, unsubstituted orsubstituted di-(C₁-C₆)alkylamino, unsubstituted or substituted C₅-C₁₀aryl, unsubstituted or substituted heteroaryl comprising 1-4 heteroatomsselected from N, O and S, unsubstituted or substituted C₃-C₁₀ carbocycleor unsubstituted or substituted heterocycle comprising 1-4 heteroatomsselected from N, O and S.

For example, each R₄ is unsubstituted or substituted C₁-C₆ alkoxyl.

For example, each R₄ is unsubstituted methoxyl.

For example, any two adjacent R₄'s, together with the atoms to whichthey are attached, form a 5- to 7-member ring selected from furanyl,pyrrolyl, thiophenyl, pyrazolyl, imidazoly, oxazolyl, isoxazolyl,triazolyl, oxadiazolyl, isoxadiazolyl, thiadiazolyl, tetrazolyl,pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolidinyl,imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl,triazolidinyl, tetrahyrofuranyl, piperidinyl, piperazinyl, morpholinyl,and the like, and is optionally substituted.

The present invention provides compounds of formulae II, IIa and IIIb:

or a salt or ester thereof, wherein:

one of Z₁ and Z₂ is CR₃ the other is N;

Z is —(CH₂)_(n)—, —CH₂—O—(CH₂)_(n)— or a bond;

m is 0, 1, 2, 3, 4;

n is 1, 2, 3, 4, 5, 6;

R₃ is H, halogen, unsubstituted or substituted C₁-C₈ alkyl,unsubstituted or substituted C₅-C₁₀ aryl, unsubstituted or substitutedheteroaryl comprising 1-4 heteroatoms selected from N, O and S,unsubstituted or substituted C₃-C₁₀ carbocycle or unsubstituted orsubstituted heterocycle comprising 1-4 heteroatoms selected from N, Oand S;

each R₄ is independently hydroxyl, halogen, unsubstituted or substitutedC₁-C₆ alkyl, unsubstituted or substituted C₁-C₆ alkoxyl, amino,unsubstituted or substituted C₁-C₆ alkylamino, unsubstituted orsubstituted di-(C₁-C₆)alkylamino, unsubstituted or substituted C₅-C₁₀aryl, unsubstituted or substituted heteroaryl comprising 1-4 heteroatomsselected from N, O and S, unsubstituted or substituted C₃-C₁₀carbocycle, unsubstituted or substituted heterocycle comprising 1-4heteroatoms selected from N, O and S or any two adjacent R₄'s, togetherwith the atoms to which they are attached, form a 5- to 7-member ringoptionally comprising 1-4 optionally comprising 1-4 heteroatoms selectedfrom N, O and S; and

R₅ is H, unsubstituted or substituted C₁-C₆ alkyl, unsubstituted orsubstituted C₅-C₁₀ aryl, unsubstituted or substituted heteroarylcomprising 1-4 heteroatoms selected from N, O and S, unsubstituted orsubstituted C₃-C₁₀ carbocycle or unsubstituted or substitutedheterocycle comprising 1-4 heteroatoms selected from N, O and S.

For example, Z is a bond.

For example, Z is —(CH₂)_(n)—.

For example, n is 1, 2 or 3.

For example, when Z is a bond R₅ cannot be H.

F or example, Z₁ is CR₃ where R₃ is H and Z₂ is N.

For example, Z₁ is N and Z₂ is CR₃.

For example, R₃ is H.

For example, R₅ is H.

For example, R₅ is unsubstituted or substituted methyl, ethyl, n-propyl,i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl or n-hexyl.

For example, R₅ is C₅-C₁₀ aryl, and is optionally substituted.

For example, R₅ is unsubstituted phenyl.

For example, R₅ is phenyl substituted with one or more groups, each ofwhich can be the same or different, selected from hydroxyl, halogen,cyano, unsubstituted or substituted C₁-C₆ alkyl, unsubstituted orsubstituted C₁-C₆ alkoxyl, amino, unsubstituted or substituted C₁-C₆alkylamino, or unsubstituted or substituted di(C₁-C₆)alkylamino.

For example, R₅ is phenyl substituted with one or more groups, each ofwhich can be the same or different, selected from unsubstituted orsubstituted, straight-chain or branched C₁-C₆ alkyl.

For example, R₅ is phenyl substituted with one or more groups, each ofwhich can be the same or different, selected from unsubstituted orsubstituted methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl,t-butyl, n-pentyl, s-pentyl and n-hexyl.

For example, R₅ is phenyl substituted with one or more groups, each ofwhich can be the same or different, selected from substituted C₁-C₆alkyl each of which is optionally substituted with halogen (e.g.,fluorine (e.g., the substituted alkyl is —CF₃ or —CHF₂), chlorine,bromine and iodine).

For example, R₅ is phenyl substituted with one or more groups, each ofwhich can be the same or different, selected from trifluoromethyl andtrichloromethyl.

For example, R₅ is phenyl substituted with one or more groups, each ofwhich can be the same or different, selected from fluorine, chlorine,bromine and iodine.

For example, R₅ is phenyl substituted with two groups.

For example, R₅ is phenyl substituted with one group.

For example, R₅ is heteroaryl selected from furanyl, pyrrolyl,thiophenyl, pyrazolyl, imidazoly, oxazolyl, isoxazolyl, triazolyl,thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl,naphthyridinyl, purinyl and indolyl, and is optionally substituted.

For example, R₅ is cyclobutyl, cyclopentyl or cyclohexyl, and isoptionally substituted.

For example, R₅ is heterocycle selected from pyrrolidinyl,imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl,triazolidinyl, tetrahyrofuranyl, piperidinyl, piperazinyl andmorpholinyl, and is optionally substituted.

For example, m is 0.

For example, m is 1 or 2.

For example, each R₄ is independently unsubstituted or substitutedmethyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl,s-pentyl or n-hexyl.

For example, each R₄ is independently unsubstituted or substituted C₁-C₆alkoxyl.

For example, each R₄ is unsubstituted methoxyl.

For example, each R₄ is independently trifluoromethyl ortrichloromethyl.

For example, each R₄ is independently fluorine, chlorine, bromine oriodine.

For example, R₃ is H, m is 2, R₄ is methoxyl, Z is a bond and R₅ issubstituted phenyl.

For example, R₃ is H, m is 2, R₄ is methoxyl, Z is a bond and R₅ ischlorofluorophenyl.

For example, R₃ is H, m is 2, R₄ is methoxyl, Z is a bond and R₅ istrifluoromethylphenyl.

For example, R₃ is H, m is 2, R₄ is methoxyl, Z is a bond and R₅ ischlorophenyl.

For example, R₃ is H, m is 2, R₄ is methoxyl, Z is —(CH₂)_(n), n is 2and R₅ is unsubstituted phenyl.

For example, m is 2, R₄ is methoxyl, Z is a bond and R₅ ischlorofluorophenyl.

For example, m is 2, R₄ is methoxyl, Z is a bond and R₅ istrifluoromethylphenyl.

For example, m is 2, R₄ is methoxyl, Z is a bond and R₅ is chlorophenyl.

For example, m is 2, R₄ is methoxyl, Z is —(CH₂)_(n), n is 2 and R₅ isunsubstituted phenyl.

Representative compounds of the present invention include compoundslisted in Tables 1 and 2.

TABLE 1

As used herein, “alkyl”, “C₁, C₂, C₃, C₄, C₅ or C₆ alkyl” or “C₁-C₆alkyl” is intended to include C₁, C₂, C₃, C₄, C₅ or C₆ straight chain(linear) saturated aliphatic hydrocarbon groups and C₃, C₄, C₅ or C₆branched saturated aliphatic hydrocarbon groups. For example, C₁-C₆alkyl is intended to include C₁, C₂, C₃, C₄, C₅ and C₆ alkyl groups.Examples of alkyl include, moieties having from one to six carbon atoms,such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl,s-butyl, t-butyl, n-pentyl, s-pentyl or n-hexyl.

In certain embodiments, a straight chain or branched alkyl has six orfewer carbon atoms (e.g., C₁-C₆ for straight chain, C₃-C₆ for branchedchain), and in another embodiment, a straight chain or branched alkylhas four or fewer carbon atoms.

“Heteroalkyl” groups are alkyl groups, as defined above, that have anoxygen, nitrogen, sulfur or phosphorous atom replacing one or morehydrocarbon backbone carbon atoms.

As used herein, the term “cycloalkyl”, “C₃, C₄, C₅, C₆, C₇ or C₈cycloalkyl” or “C₃-C₈ cycloalkyl” is intended to include hydrocarbonrings having from three to eight carbon atoms in their ring structure.In one embodiment, a cycloalkyl group has five or six carbons in thering structure.

The term “substituted alkyl” refers to alkyl moieties havingsubstituents replacing one or more hydrogen atoms on one or more carbonsof the hydrocarbon backbone. Such substituents can include, for example,alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, amino (including alkylamino,dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety. Cycloalkyls can be further substituted, e.g.,with the substituents described above. An “alkylaryl” or an “aralkyl”moiety is an alkyl substituted with an aryl (e.g., phenylmethyl(benzyl)).

Unless the number of carbons is otherwise specified, “lower alkyl”includes an alkyl group, as defined above, having from one to six, or inanother embodiment from one to four, carbon atoms in its backbonestructure. “Lower alkenyl” and “lower alkynyl” have chain lengths of,for example, two to six or of two to four carbon atoms.

“Alkenyl” includes unsaturated aliphatic groups analogous in length andpossible substitution to the alkyls described above, but that contain atleast one double bond. For example, the term “alkenyl” includes straightchain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl,hexenyl, heptenyl, octenyl, nonenyl, decenyl), branched alkenyl groups,cycloalkenyl (e.g., alicyclic) groups (e.g., cyclopropenyl,cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl oralkenyl substituted cycloalkenyl groups, and cycloalkyl or cycloalkenylsubstituted alkenyl groups. In certain embodiments, a straight chain orbranched alkenyl group has six or fewer carbon atoms in its backbone(e.g., C₂-C₆ for straight chain, C₃-C₆ for branched chain). Likewise,cycloalkenyl groups may have from five to eight carbon atoms in theirring structure, and in one embodiment, cycloalkenyl groups have five orsix carbons in the ring structure. The term “C₂-C₆” includes alkenylgroups containing two to six carbon atoms. The term “C₃-C₆” includesalkenyl groups containing three to six carbon atoms.

“Heteroalkenyl” includes alkenyl groups, as defined herein, having anoxygen, nitrogen, sulfur or phosphorous atom replacing one or morehydrocarbon backbone carbons.

The term “substituted alkenyl” refers to alkenyl moieties havingsubstituents replacing one or more hydrogen atoms on one or morehydrocarbon backbone carbon atoms. Such substituents can include, forexample, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, amino (including alkylamino,dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic orheteroaromatic moiety.

“Alkynyl” includes unsaturated aliphatic groups analogous in length andpossible substitution to the alkyls described above, but which containat least one triple bond. For example, “alkynyl” includes straight chainalkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl,heptynyl, octynyl, nonynyl, decynyl), branched alkynyl groups, andcycloalkyl or cycloalkenyl substituted alkynyl groups. In certainembodiments, a straight chain or branched alkynyl group has six or fewercarbon atoms in its backbone (e.g., C₂-C₆ for straight chain, C₃-C₆ forbranched chain). The term “C₂-C₆” includes alkynyl groups containing twoto six carbon atoms. The term “C₃-C₆” includes alkynyl groups containingthree to six carbon atoms.

“Heteroalkynyl” includes alkynyl groups, as defined herein, having anoxygen, nitrogen, sulfur or phosphorous atom replacing one or morehydrocarbon backbone carbons.

The term “substituted alkynyl” refers to alkynyl moieties havingsubstituents replacing one or more hydrogen atoms on one or morehydrocarbon backbone carbon atoms. Such substituents can include, forexample, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, amino (including alkylamino,dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety.

“Aryl” includes groups with aromaticity, including “conjugated”, ormulticyclic, systems with at least one aromatic ring. Examples includephenyl, benzyl, etc.

“Heteroaryl” groups are aryl groups, as defined above, having from oneto four heteroatoms in the ring structure, and may also be referred toas “aryl heterocycles” or “heteroaromatics”. As used herein, the term“heteroaryl” is intended to include a stable 5-, 6-, or 7-memberedmonocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromaticheterocyclic ring which consists of carbon atoms and one or moreheteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, ore.g., 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from thegroup consisting of nitrogen, oxygen and sulfur. The nitrogen atom maybe substituted or unsubstituted (i.e., N or NR wherein R is H or othersubstituents, as defined). The nitrogen and sulfur heteroatoms mayoptionally be oxidized (i.e., N→O and S(O)_(p), where p=1 or 2). It isto be noted that total number of S and O atoms in the aromaticheterocycle is not more than 1.

Examples of heteroaryl groups include pyrrole, furan, thiophene,thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole,oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and thelike.

Furthermore, the terms “aryl” and “heteroaryl” include multicyclic aryland heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene,benzoxazole, benzodioxazole, benzothiazole, benzoimidazole,benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline,naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine,indolizine.

In the case of multicyclic aromatic rings, only one of the rings needsto be aromatic (e.g., 2,3-dihydroindole), although all of the rings maybe aromatic (e.g., quinoline). The second ring can also be fused orbridged.

The aryl or heteroaryl aromatic ring can be substituted at one or morering positions with such substituents as described above, for example,alkyl, alkenyl, akynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl,alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl,alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl,phosphate, phosphonato, phosphinato, amino (including alkylamino,dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety. Aryl groups can also be fused or bridged withalicyclic or heterocyclic rings, which are not aromatic so as to form amulticyclic system (e.g., tetralin, methylenedioxyphenyl).

As used herein, “carbocycle” or “carbocyclic ring” is intended toinclude any stable monocyclic, bicyclic or tricyclic ring having thespecified number of carbons, any of which may be saturated, unsaturated,or aromatic. For example, a C₃-C₁₄ carbocycle is intended to include amonocyclic, bicyclic or tricyclic ring having 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13 or 14 carbon atoms. Examples of carbocycles include, but arenot limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl,cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl,adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, fluorenyl, phenyl,naphthyl, indanyl, adamantyl and tetrahydronaphthyl. Bridged rings arealso included in the definition of carbocycle, including, for example,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane and[2.2.2]bicyclooctane. A bridged ring occurs when one or more carbonatoms link two non-adjacent carbon atoms. In one embodiment, bridgerings are one or two carbon atoms. It is noted that a bridge alwaysconverts a monocyclic ring into a tricyclic ring. When a ring isbridged, the substituents recited for the ring may also be present onthe bridge. Fused (e.g., naphthyl, tetrahydronaphthyl) and spiro ringsare also included.

As used herein, “heterocycle” includes any ring structure (saturated orpartially unsaturated) which contains at least one ring heteroatom(e.g., N, O or S). Examples of heterocycles include, but are not limitedto, morpholine, pyrrolidine, tetrahydrothiophene, piperidine, piperazineand tetrahydrofuran.

Examples of heterocyclic groups include, but are not limited to,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl,naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,4-oxadiazol5(4H)-one, oxazolidinyl, oxazolyl, oxindolyl,pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl,pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl,quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl.

The term “substituted”, as used herein, means that any one or morehydrogen atoms on the designated atom is replaced with a selection fromthe indicated groups, provided that the designated atom's normal valencyis not exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogen atoms on the atomare replaced. Keto substituents are not present on aromatic moieties.Ring double bonds, as used herein, are double bonds that are formedbetween two adjacent ring atoms (e.g., C═C, C═N or N═N). “Stablecompound” and “stable structure” are meant to indicate a compound thatis sufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom in thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchformula. Combinations of substituents and/or variables are permissible,but only if such combinations result in stable compounds.

When any variable (e.g., R₄) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R₄ moieties,then the group may optionally be substituted with up to two R₄ moietiesand R₄ at each occurrence is selected independently from the definitionof R₄. Also, combinations of substituents and/or variables arepermissible, but only if such combinations result in stable compounds.

The term “hydroxy” or “hydroxyl” includes groups with an —OH or —O⁻.

As used herein, “halo” or “halogen” refers to fluoro, chloro, bromo andiodo. The term “perhalogenated” generally refers to a moiety wherein allhydrogen atoms are replaced by halogen atoms.

The term “carbonyl” or “carboxy” includes compounds and moieties whichcontain a carbon connected with a double bond to an oxygen atom.Examples of moieties containing a carbonyl include, but are not limitedto, aldehydes, ketones, carboxylic acids, amides, esters, anhydrides,etc.

“Acyl” includes moieties that contain the acyl radical (—C(O)—) or acarbonyl group. “Substituted acyl” includes acyl groups where one ormore of the hydrogen atoms are replaced by, for example, alkyl groups,alkynyl groups, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,phosphonato, phosphinato, amino (including alkylamino, dialkylamino,arylamino, diarylamino and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety.

“Aroyl” includes moieties with an aryl or heteroaromatic moiety bound toa carbonyl group. Examples of aroyl groups include phenylcarboxy,naphthyl carboxy, etc.

“Alkoxyalkyl”, “alkylaminoalkyl” and “thioalkoxyalkyl” include alkylgroups, as described above, wherein oxygen, nitrogen or sulfur atomsreplace one or more hydrocarbon backbone carbon atoms.

The term “alkoxy” or “alkoxyl” includes substituted and unsubstitutedalkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom.Examples of alkoxy groups or alkoxyl radicals include, but are notlimited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxygroups. Examples of substituted alkoxy groups include halogenated alkoxygroups. The alkoxy groups can be substituted with groups such asalkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,phosphonato, phosphinato, amino (including alkylamino, dialkylamino,arylamino, diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moieties. Examples of halogen substituted alkoxygroups include, but are not limited to, fluoromethoxy, difluoromethoxy,trifluoromethoxy, chloromethoxy, dichloromethoxy and trichloromethoxy.

The term “ether” or “alkoxy” includes compounds or moieties whichcontain an oxygen bonded to two carbon atoms or heteroatoms. Forexample, the term includes “alkoxyalkyl”, which refers to an alkyl,alkenyl, or alkynyl group covalently bonded to an oxygen atom which iscovalently bonded to an alkyl group.

The term “ester” includes compounds or moieties which contain a carbonor a heteroatom bound to an oxygen atom which is bonded to the carbon ofa carbonyl group. The term “ester” includes alkoxycarboxy groups such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,pentoxycarbonyl, etc.

The term “thioalkyl” includes compounds or moieties which contain analkyl group connected with a sulfur atom. The thioalkyl groups can besubstituted with groups such as alkyl, alkenyl, alkynyl, halogen,hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, carboxyacid, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, amino (includingalkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic moieties.

The term “thiocarbonyl” or “thiocarboxy” includes compounds and moietieswhich contain a carbon connected with a double bond to a sulfur atom.

The term “thioether” includes moieties which contain a sulfur atombonded to two carbon atoms or heteroatoms. Examples of thioethersinclude, but are not limited to alkthioalkyls, alkthioalkenyls andalkthioalkynyls. The term “alkthioalkyls” include moieties with analkyl, alkenyl or alkynyl group bonded to a sulfur atom which is bondedto an alkyl group. Similarly, the term “alkthioalkenyls” refers tomoieties wherein an alkyl, alkenyl or alkynyl group is bonded to asulfur atom which is covalently bonded to an alkenyl group; andalkthioalkynyls” refers to moieties wherein an alkyl, alkenyl or alkynylgroup is bonded to a sulfur atom which is covalently bonded to analkynyl group.

As used herein, “amine” or “amino” includes moieties where a nitrogenatom is covalently bonded to at least one carbon or heteroatom.“Alkylamino” includes groups of compounds wherein nitrogen is bound toat least one alkyl group. Examples of alkylamino groups includebenzylamino, methylamino, ethylamino, phenethylamino, etc.“Dialkylamino” includes groups wherein the nitrogen atom is bound to atleast two additional alkyl groups. Examples of dialkylamino groupsinclude, but are not limited to, dimethylamino and diethylamino.“Arylamino” and “diarylamino” include groups wherein the nitrogen isbound to at least one or two aryl groups, respectively.“Alkylarylamino”, “alkylaminoaryl” or “arylaminoalkyl” refers to anamino group which is bound to at least one alkyl group and at least onearyl group. “Alkaminoalkyl” refers to an alkyl, alkenyl, or alkynylgroup bound to a nitrogen atom which is also bound to an alkyl group.“Acylamino” includes groups wherein nitrogen is bound to an acyl group.Examples of acylamino include, but are not limited to,alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.

The term “amide” or “aminocarboxy” includes compounds or moieties thatcontain a nitrogen atom that is bound to the carbon of a carbonyl or athiocarbonyl group. The term includes “alkaminocarboxy” groups thatinclude alkyl, alkenyl or alkynyl groups bound to an amino group whichis bound to the carbon of a carbonyl or thiocarbonyl group. It alsoincludes “arylaminocarboxy” groups that include aryl or heteroarylmoieties bound to an amino group that is bound to the carbon of acarbonyl or thiocarbonyl group. The terms “alkylaminocarboxy”,“alkenylaminocarboxy”, “alkynylaminocarboxy” and “arylaminocarboxy”include moieties wherein alkyl, alkenyl, alkynyl and aryl moieties,respectively, are bound to a nitrogen atom which is in turn bound to thecarbon of a carbonyl group. Amides can be substituted with substituentssuch as straight chain alkyl, branched alkyl, cycloalkyl, aryl,heteroaryl or heterocycle. Substituents on amide groups may be furthersubstituted.

As used herein, “alkyl linker” is intended to include C₁, C₂, C₃, C₄, C₅or C₆ straight chain (linear) saturated aliphatic hydrocarbon groups andC₃, C₄, C₅ or C₆ branched saturated aliphatic hydrocarbon groups. Forexample, C₁-C₆ alkyl linker is intended to include C₁, C₂, C₃, C₄, C₅and C₆ alkyl linker groups. Examples of alkyl linker include, moietieshaving from one to six carbon atoms, such as, but not limited to, methyl(—CH₂—), ethyl (—CH₂CH₂—)₅ n-propyl (—CH₂CH₂CH₂—), i-propyl(—CHCH₃CH₂—), n-butyl (—CH₂CH₂CH₂CH₂—), s-butyl (—CHCH₃CH₂CH₂—), i-butyl(—C(CH₃)₂CH₂—), n-pentyl (—CH₂CH₂CH₂CH₂CH₂—), s-pentyl(—CHCH₃CH₂CH₂CH₂—) or n-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₂—).

Compounds of the present invention that contain nitrogens can beconverted to N-oxides by treatment with an oxidizing agent (e.g.,3-chloroperoxybenzoic acid (m-CPBA) and/or hydrogen peroxides) to affordother compounds of the present invention. Thus, all shown and claimednitrogen-containing compounds are considered, when allowed by valencyand structure, to include both the compound as shown and its N-oxidederivative (which can be designated as N→O or N⁺—O⁻). Furthermore, inother instances, the nitrogens in the compounds of the present inventioncan be converted to N-hydroxy or N-alkoxy compounds. For example,N-hydroxy compounds can be prepared by oxidation of the parent amine byan oxidizing agent such as m-CPBA. All shown and claimednitrogen-containing compounds are also considered, when allowed byvalency and structure, to cover both the compound as shown and itsN-hydroxy (i.e., N—OH) and N-alkoxy (i.e., N—OR, wherein R issubstituted or unsubstituted C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl,3-14-membered carbocycle or 3-14-membered heterocycle) derivatives.

In the present specification, the structural formula of the compoundrepresents a certain isomer for convenience in some cases, but thepresent invention includes all isomers, such as geometrical isomers,optical isomers based on an asymmetrical carbon, stereoisomers,tautomers, and the like. In addition, a crystal polymorphism may bepresent for the compounds represented by the formula. It is noted thatany crystal form, crystal form mixture, or anhydride or hydrate thereofis included in the scope of the present invention. Furthermore,so-called metabolite which is produced by degradation of the presentcompound in vivo is included in the scope of the present invention.

“Isomerism” means compounds that have identical molecular formulae butdiffer in the sequence of bonding of their atoms or in the arrangementof their atoms in space. Isomers that differ in the arrangement of theiratoms in space are termed “stereoisomers”. Stereoisomers that are notmirror images of one another are termed “diastereoisomers”, andstereoisomers that are non-superimposable mirror images of each otherare termed “enantiomers” or sometimes optical isomers. A mixturecontaining equal amounts of individual enantiomeric forms of oppositechirality is termed a “racemic mixture”.

A carbon atom bonded to four nonidentical substituents is termed a“chiral center”.

“Chiral isomer” means a compound with at least one chiral center.Compounds with more than one chiral center may exist either as anindividual diastereomer or as a mixture of diastereomers, termed“diastereomeric mixture”. When one chiral center is present, astereoisomer may be characterized by the absolute configuration (R or S)of that chiral center. Absolute configuration refers to the arrangementin space of the substituents attached to the chiral center. Thesubstituents attached to the chiral center under consideration areranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog.(Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahnet al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951(London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem.Educ. 1964, 41, 116).

“Geometric isomer” means the diastereomers that owe their existence tohindered rotation about double bonds. These configurations aredifferentiated in their names by the prefixes cis and trans, or Z and E,which indicate that the groups are on the same or opposite side of thedouble bond in the molecule according to the Cahn-Ingold-Prelog rules.

Furthermore, the structures and other compounds discussed in thisinvention include all atropic isomers thereof. “Atropic isomers” are atype of stereoisomer in which the atoms of two isomers are arrangeddifferently in space. Atropic isomers owe their existence to arestricted rotation caused by hindrance of rotation of large groupsabout a central bond. Such atropic isomers typically exist as a mixture,however as a result of recent advances in chromatography techniques; ithas been possible to separate mixtures of two atropic isomers in selectcases.

“Tautomer” is one of two or more structural isomers that exist inequilibrium and is readily converted from one isomeric form to another.This conversion results in the formal migration of a hydrogen atomaccompanied by a switch of adjacent conjugated double bonds. Tautomersexist as a mixture of a tautomeric set in solution. In solid form,usually one tautomer predominates. In solutions where tautomerization ispossible, a chemical equilibrium of the tautomers will be reached. Theexact ratio of the tautomers depends on several factors, includingtemperature, solvent and pH. The concept of tautomers that areinterconvertable by tautomerizations is called tautomerism.

Of the various types of tautomerism that are possible, two are commonlyobserved. In keto-enol tautomerism a simultaneous shift of electrons anda hydrogen atom occurs. Ring-chain tautomerism arises as a result of thealdehyde group (—CHO) in a sugar chain molecule reacting with one of thehydroxy groups (—OH) in the same molecule to give it a cyclic(ring-shaped) form as exhibited by glucose.

Common tautomeric pairs are: ketone-enol, amide-nitrile, lactam-lactim,amide-imidic acid tautomerism in heterocyclic rings (e.g., innucleobases such as guanine, thymine and cytosine), amine-enamine andenamine-enamine.

It is to be understood that the compounds of the present invention maybe depicted as different tautomers. It should also be understood thatwhen compounds have tautomeric forms, all tautomeric forms are intendedto be included in the scope of the present invention, and the naming ofthe compounds does not exclude any tautomer form.

The term “crystal polymorphs”, “polymorphs” or “crystal forms” meanscrystal structures in which a compound (or a salt or solvate thereof)can crystallize in different crystal packing arrangements, all of whichhave the same elemental composition. Different crystal forms usuallyhave different X-ray diffraction patterns, infrared spectral, meltingpoints, density hardness, crystal shape, optical and electricalproperties, stability and solubility. Recrystallization solvent, rate ofcrystallization, storage temperature, and other factors may cause onecrystal form to dominate. Crystal polymorphs of the compounds can beprepared by crystallization under different conditions.

Additionally, the compounds of the present invention, for example, thesalts of the compounds, can exist in either hydrated or unhydrated (theanhydrous) form or as solvates with other solvent molecules. Nonlimitingexamples of hydrates include monohydrates, dihydrates, etc. Nonlimitingexamples of solvates include ethanol solvates, acetone solvates, etc.

“Solvate” means solvent addition forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate; and if the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one molecule of the substance inwhich the water retains its molecular state as H₂O.

As used herein, the term “analog” refers to a chemical compound that isstructurally similar to another but differs slightly in composition (asin the replacement of one atom by an atom of a different element or inthe presence of a particular functional group, or the replacement of onefunctional group by another functional group). Thus, an analog is acompound that is similar or comparable in function and appearance, butnot in structure or origin to the reference compound.

As defined herein, the term “derivative” refers to compounds that have acommon core structure, and are substituted with various groups asdescribed herein. For example, all of the compounds represented byformulae I, Ia and Ib are substituted heterocyclic compounds and haveformula I, Ia or Ib as a common core. For example, all of the compoundsrepresented by formulae II, IIa and IIb are substitutedtetrahydroisoquinoline compounds and have formula II, IIa or IIb as acommon core.

The term “bioisostere” refers to a compound resulting from the exchangeof an atom or of a group of atoms with another, broadly similar, atom orgroup of atoms. The objective of a bioisosteric replacement is to createa new compound with similar biological properties to the parentcompound. The bioisosteric replacement may be physicochemically ortopologically based. Examples of carboxylic acid bioisosteres include,but are not limited to, acyl sulfonimides, tetrazoles, sulfonates andphosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176,1996.

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include tritium anddeuterium, and isotopes of carbon include C-13 and C-14.

2. Synthesis of Compounds of the Present Invention

The present invention provides methods for the synthesis of thecompounds of formula I, Ia, Ib, II, IIa or IIb. The present inventionalso provides detailed methods for the synthesis of various disclosedcompounds of the present invention according to the following schemesand as shown in the Examples.

Throughout the description, where compositions are described as having,including, or comprising specific components, it is contemplated thatcompositions also consist essentially of, or consist of, the recitedcomponents. Similarly, where methods or processes are described ashaving, including, or comprising specific process steps, the processesalso consist essentially of, or consist of, the recited processingsteps. Further, it should be understood that the order of steps or orderfor performing certain actions is immaterial so long as the inventionremains operable. Moreover, two or more steps or actions can beconducted simultaneously.

The synthetic processes of the invention can tolerate a wide variety offunctional groups, therefore various substituted starting materials canbe used. The processes generally provide the desired final compound ator near the end of the overall process, although it may be desirable incertain instances to further convert the compound to a pharmaceuticallyacceptable salt, ester or prodrug thereof.

Compounds of the present invention can be prepared in a variety of waysusing commercially available starting materials, compounds known in theliterature, or from readily prepared intermediates, by employingstandard synthetic methods and procedures either known to those skilledin the art, or which will be apparent to the skilled artisan in light ofthe teachings herein. Standard synthetic methods and procedures for thepreparation of organic molecules and functional group transformationsand manipulations can be obtained from the relevant scientificliterature or from standard textbooks in the field. Although not limitedto any one or several sources, classic texts such as Smith, M. B.,March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms,and Structure, 5^(th) edition, John Wiley & Sons: New York, 2001; andGreene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis,3^(rd) edition, John Wiley & Sons: New York, 1999, incorporated byreference herein, are useful and recognized reference textbooks oforganic synthesis known to those in the art. The following descriptionsof synthetic methods are designed to illustrate, but not to limit,general procedures for the preparation of compounds of the presentinvention.

Compounds of the present invention can be conveniently prepared by avariety of methods familiar to those skilled in the art. The compoundsof this invention with formula I, Ia, Ib, II, IIa or IIb may be preparedaccording to the following procedures from commercially availablestarting materials or starting materials which can be prepared usingliterature procedures. These procedures show the preparation ofrepresentative compounds of this invention.

General Procedure 1

Compounds of formula I, Ia or Ib can be prepared by a variety of methodsfamiliar to those skilled in the art. One common route is illustrated inscheme 1 above. BOC protected2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepines (1) which are commerciallyavailable or can be readily synthesized using literature proceduresknown to those skilled in art can be reductively aminated using anappropriate aldehyde such as benzaldehyde or phenethylbenzaldehde and areducing agent such as sodium triacetoxyborohydride or sodiumcyanoborohydride in a suitable solvent such as tetrahydrofuran ordioxane at temperatures ranging from 0-80° C., typically 50° C., to givecompound (2). Deprotection of compound (2) can be achieved using anappropriate acid such as hydrochloric acid or trifluoroacetic acid in asuitable solvent such as dioxane or dichloromethane at temperaturesranging from 0-80° C., typically ambient temperature, to give compound(3). Compound (3) can be alkylated with a suitable heterocyclic halidesuch as 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-amine or6-chloro-9H-purin-2-amine in the presence of a suitable base such astriethylamine or diisopropylethylamine in a suitable solvent such asdimethylsulfoxide, dimethylformamide or dimethylacetamide attemperatures ranging from 25-150° C., typically 25° C., 80° C. or 120°C., to furnish compounds of formula I, Ia or Ib.

Step 1

Aldehyde solution (0.25 M in anhydrous dichloroethane), a stock solutionof tert-butyl 2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carboxylate(0.25 M in anhydrous dichloroethane) and a stock slurry of NaBH(OAc)₃(0.25 M in anhydrous dichloroethane) were prepared. In 2 dram vials weredispensed 400 μl of tert-butyl2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carboxylate solution and 480μl of aldehyde solution (1.2 eq.). The vials were vortexed then 1 ml ofNaBH(OAc)₃ slurry solution (2.5 eq.) was dispensed to each vial. Thevials were capped and shaken at 50° C. for 24-40 hours. The vials wereuncapped and 1.5 ml of 10% ammonia solution was added. The vials wererecapped, vortexed, uncapped then let to sit at room temperature for 1-2hours to allow for degassing. The vials were recapped, vortexed andcentrifuged. The bottom layer (2.8 ml) was removed and transferred intocollection vials. The aqueous phases were extracted with 2.5 ml ofdichloroethane (vortex, centrifugation). The combined extracts weredried down in a Genevac (water mixture settings). The products were thenused without further purification in steps 2 and 3.

Step 2 and 3.

The products from Step 1 were dissolved 1 ml of dichloroethane then 500μl of HCl in dioxane was dispensed to each vial. The vials were shakenat room temperature for 20 hours then dried down using a Genevac. Thecrude products were used directly in step 3.

Step 3

A stock solution (0.5 M) of either4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-amine or6-chloro-9H-purin-2-amine in dimethylsufoxide was prepared thendispensed (800 4 eq.) to each of the products from the previous step.Diisopropylethylamine (1 ml) was added to each vial. The vials werecapped then shaken at 120° C. for 24 hours (vortexing may be necessaryto ensure complete dissolution). The solvent was removed using Genevacon DMSO setting until dryness. The residues in the vials were dissolvedin 1 ml of dimethylsulfoxide. Products purified by reverse phasechromatography on a preparative LC/UV/MS system using a mass triggeredfractionation. Compounds were eluted from the HPLC column (Maccel120-10-C18 SH 10 μm 20 mmID×50 mm) at 88 ml/min with 5-95acetonitrile/water gradient using 0.1% TFA as modifier. All thecompounds were characterized by LC/MS.

General Procedure 2

Compounds of formula II, IIa or IIb can be prepared by a variety ofmethods familiar to those skilled in the art. One common route isillustrated in Scheme 2.

Step 1

Compounds of formula (4) are commercially available or can be readilysynthesized using literature procedures known to those skilled in artand can be converted to compounds of formula (5) using Pictet-Spenglerchemistry as cited in the references: Pictet, A.; Spengler, T., Ber.,1911, 44, 2030; Whaley, W. M.; Govindachari, T. R., Org. React., 1951,6, 74; Rousseau, J-F.; Dodd, R. H., J. Org. Chem., 1998, 63, 2731-2737and Leonard, J.; Hague, A. B.; Jones, M. F. Tetrahedron Lett., 1997, 38,3071-3074.

Step 2:

Compounds of formula II, IIa or IIb can be prepared from compounds offormula (5) by alkylation with a suitable heterocyclic halide such as4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-amine or6-chloro-9H-purin-2-amine in the presence of a suitable base such astriethylamine or diisopropylethylamine in a suitable solvent such asdimethylsulfoxide, dimethylformamide or dimethylacetamide attemperatures ranging from 25-150° C., typically 25° C., 80° C. or 120°C., to furnish compounds of formula II, IIa or IIb.

General Procedure 3

Compounds of formula I, Ia or Ib can also be prepared according toScheme 3.

Anilines of formula (6) that are commercially available or can bereadily synthesized using literature procedures known to those skilledin art can be reductively aminated using an appropriate aldehyde such asbenzaldehyde or phenethylbenzaldehde and a reducing agent such as sodiumtriacetoxyborohydride or sodium cyanoborohydride in a suitable solventsuch as tetrahydrofuran or dioxane at temperatures ranging from 0-80°C., typically 50° C. The resulting amines can be acylated using anappropriately substituted glycine such as N-boc glycine or N-boc alanineand a coupling agent such as dicyclohexylcarbodiimide, orcarbonyldiimidazole in a suitable solvent such as tetrahydrofuran ordichloromethane dioxane at temperatures ranging from 0-80° C. Conversionof the ester functionality to an aldehyde may be achieved eitherdirectly with a suitable reducing agent such as diibutylaluminiumhydride at temperatures ranging from −78° C. to ambient in a suitablesolvent such as tetrahydrofuran or by reduction to the alcohol using asuitable reducing agent such as diibutylaluminium hydride followed byreoxidation with a suitable oxidizing agent such Dess-Martin's reagentor manganese dioxide. Deprotection of the amine with a suitabledeprotection agent such as trifluoroacetic acid in a suitable solventsuch as dichloromethane at temperatures ranging from 0-80° C. allows thecyclic amine (7) to be formed under reductive amination conditions suchas those used before. Final alkylation with a suitable heterocyclichalide such as 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-amine or6-chloro-9H-purin-2-amine in the presence of a suitable base such astriethylamine or diisopropylethylamine in a suitable solvent such asdimethylsulfoxide, dimethylformamide or dimethylacetamide attemperatures ranging from 25-150° C., typically 25° C., 80° C. or 120°C. furnishes compounds of formula I, Ia or Ib.

General Procedure 4

Compounds of formula I, Ia or Ib can also be prepared according toScheme 4.

Amines available from scheme 3 can be deprotected with a suitabledeprotection agent such as trifluoroacetic acid in a suitable solventsuch as dichloromethane at temperatures ranging from 0-80° C. thenreacted with a suitable heterocyclic halide such as4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-amine or6-chloro-9H-purin-2-amine in the presence of a suitable base such astriethylamine or diisopropylethylamine in a suitable solvent such asdimethylsulfoxide, dimethylformamide or dimethylacetamide attemperatures ranging from 25-150° C., typically 25° C., 80° C. or 120°C. Compounds of formula I, Ia or Ib may then be made either by cyclizingdirectly by heating at a suitable temperature such as 50-250° C. orheating with a lewis acid catalyst such as boron trifluoride-etherate,zinc chloride or magnesium chloride. Alternatively the ester may befirst hydrolyzed using suitable hydrolysis conditions such as sodium orlithium hydroxide at temperatures ranging from 25-250° C. andsubsequently cyclizing a coupling agent such asdicyclohexylcarbodiimide, or carbonyldiimidazole in a suitable solventsuch as tetrahydrofuran or dichloromethane dioxane at temperaturesranging from 0-80° C.

General Procedure 5

Compounds of formula I, Ia or Ib can also be prepared according toScheme 5.

Amides available from scheme 4 can be converted to their thioamides witha suitable reagent such as phosphorus pentasulfide in a suitable solventsuch as toluene at temperatures ranging from 25-250° C. The thioamidescan be converted to their amines by using a desulfurization reagent suchas rainy-nickel in a suitable solvent such as ethanol at temperaturesranging from 25 to the boiling pont of the solvent. Final cyclizationmade either by cyclizing directly by heating at a suitable temperaturesuch as 50-250° C. or heating with a lewis acid catalyst such as borontrifluoride-etherate, zinc chloride or magnesium chloride. Alternativelythe ester may be first hydrolyzed using suitable hydrolysis conditionssuch as sodium or lithium hydroxide at temperatures ranging from 25-250°C. and subsequently cyclizing a coupling agent such asdicyclohexylcarbodiimide, or carbonyldiimidazole in a suitable solventsuch as tetrahydrofuran or dichloromethane dioxane at temperaturesranging from 0-80° C. to furnish compounds of formula I, Ia or Ib.

3. Methods of Treatment

The present invention provides methods for the treatment of a cellproliferative disorder in a subject in need thereof by administering toa subject in need of such treatment, a therapeutically effective amountof a compound of the present invention, or a pharmaceutically acceptablesalt, prodrug, metabolite, polymorph or solvate thereof. The cellproliferative disorder can be cancer or a precancerous condition. Thepresent invention further provides the use of a compound of the presentinvention, or a pharmaceutically acceptable salt, prodrug, metabolite,polymorph or solvate thereof, for the preparation of a medicament usefulfor the treatment of a cell proliferative disorder.

The present invention also provides methods of protecting against a cellproliferative disorder in a subject in need thereof by administering atherapeutically effective amount of compound of the present invention,or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph orsolvate thereof, to a subject in need of such treatment. The cellproliferative disorder can be cancer or a precancerous condition. Thepresent invention also provides the use of compound of the presentinvention, or a pharmaceutically acceptable salt, prodrug, metabolite,polymorph or solvate thereof, for the preparation of a medicament usefulfor the prevention of a cell proliferative disorder.

As used herein, a “subject in need thereof” is a subject having a cellproliferative disorder, or a subject having an increased risk ofdeveloping a cell proliferative disorder relative to the population atlarge. A subject in need thereof can have a precancerous condition.Preferably, a subject in need thereof has cancer. A “subject” includes amammal. The mammal can be e.g., any mammal, e.g., a human, primate,bird, mouse, rat, fowl, dog, cat, cow, horse, goat, camel, sheep or apig. Preferably, the mammal is a human.

As used herein, the term “cell proliferative disorder” refers toconditions in which unregulated or abnormal growth, or both, of cellscan lead to the development of an unwanted condition or disease, whichmay or may not be cancerous. Exemplary cell proliferative disorders ofthe invention encompass a variety of conditions wherein cell division isderegulated. Exemplary cell proliferative disorder include, but are notlimited to, neoplasms, benign tumors, malignant tumors, pre-cancerousconditions, in situ tumors, encapsulated tumors, metastatic tumors,liquid tumors, solid tumors, immunological tumors, hematological tumors,cancers, carcinomas, leukemias, lymphomas, sarcomas, and rapidlydividing cells. The term “rapidly dividing cell” as used herein isdefined as any cell that divides at a rate that exceeds or is greaterthan what is expected or observed among neighboring or juxtaposed cellswithin the same tissue. A cell proliferative disorder includes aprecancer or a precancerous condition. A cell proliferative disorderincludes cancer. Preferably, the methods provided herein are used totreat or alleviate a symptom of cancer. The term “cancer” includes solidtumors, as well as, hematologic tumors and/or malignancies. A “precancercell” or “precancerous cell” is a cell manifesting a cell proliferativedisorder that is a precancer or a precancerous condition. A “cancercell” or “cancerous cell” is a cell manifesting a cell proliferativedisorder that is a cancer. Any reproducible means of measurement may beused to identify cancer cells or precancerous cells. Cancer cells orprecancerous cells can be identified by histological typing or gradingof a tissue sample (e.g., a biopsy sample). Cancer cells or precancerouscells can be identified through the use of appropriate molecularmarkers.

Exemplary non-cancerous conditions or disorders include, but are notlimited to, rheumatoid arthritis; inflammation; autoimmune disease;lymphoproliferative conditions; acromegaly; rheumatoid spondylitis;osteoarthritis; gout, other arthritic conditions; sepsis; septic shock;endotoxic shock; gram-negative sepsis; toxic shock syndrome; asthma;adult respiratory distress syndrome; chronic obstructive pulmonarydisease; chronic pulmonary inflammation; inflammatory bowel disease;Crohn's disease; psoriasis; eczema; ulcerative colitis; pancreaticfibrosis; hepatic fibrosis; acute and chronic renal disease; irritablebowel syndrome; pyresis; restenosis; cerebral malaria; stroke andischemic injury; neural trauma; Alzheimer's disease; Huntington'sdisease; Parkinson's disease; acute and chronic pain; allergic rhinitis;allergic conjunctivitis; chronic heart failure; acute coronary syndrome;cachexia; malaria; leprosy; leishmaniasis; Lyme disease; Reiter'ssyndrome; acute synovitis; muscle degeneration, bursitis; tendonitis;tenosynovitis; herniated, ruptures, or prolapsed intervertebral disksyndrome; osteopetrosis; thrombosis; restenosis; silicosis; pulmonarysarcosis; bone resorption diseases, such as osteoporosis;graft-versus-host reaction; Multiple Sclerosis; lupus; fibromyalgia;AIDS and other viral diseases such as Herpes Zoster, Herpes Simplex I orII, influenza virus and cytomegalovirus; and diabetes mellitus.

Exemplary cancers include, but are not limited to, adrenocorticalcarcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer,anorectal cancer, cancer of the anal canal, appendix cancer, childhoodcerebellar astrocytoma, childhood cerebral astrocytoma, basal cellcarcinoma, skin cancer (non-melanoma), biliary cancer, extrahepatic bileduct cancer, intrahepatic bile duct cancer, bladder cancer, uringarybladder cancer, bone and joint cancer, osteosarcoma and malignantfibrous histiocytoma, brain cancer, brain tumor, brain stem glioma,cerebellar astrocytoma, cerebral astrocytoma/malignant glioma,ependymoma, medulloblastoma, supratentorial primitive neuroectodeimaltumors, visual pathway and hypothalamic glioma, breast cancer, bronchialadenomas/carcinoids, carcinoid tumor, gastrointestinal, nervous systemcancer, nervous system lymphoma, central nervous system cancer, centralnervous system lymphoma, cervical cancer, childhood cancers, chroniclymphocytic leukemia, chronic myelogenous leukemia, chronicmyeloproliferative disorders, colon cancer, colorectal cancer, cutaneousT-cell lymphoma, lymphoid neoplasm, mycosis fungoides, Seziary Syndrome,endometrial cancer, esophageal cancer, extracranial germ cell tumor,extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer,intraocular melanoma, retinoblastoma, gallbladder cancer, gastric(stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinalstromal tumor (GIST), germ cell tumor, ovarian germ cell tumor,gestational trophoblastic tumor glioma, head and neck cancer,hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer,intraocular melanoma, ocular cancer, islet cell tumors (endocrinepancreas), Kaposi Sarcoma, kidney cancer, renal cancer, kidney cancer,laryngeal cancer, acute lymphoblastic leukemia, acute myeloid leukemia,chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cellleukemia, lip and oral cavity cancer, liver cancer, lung cancer,non-small cell lung cancer, small cell lung cancer, AIDS-relatedlymphoma, non-Hodgkin lymphoma, primary central nervous system lymphoma,Waldenstram macroglobulinemia, medulloblastoma, melanoma, intraocular(eye) melanoma, merkel cell carcinoma, mesothelioma malignant,mesothelioma, metastatic squamous neck cancer, mouth cancer, cancer ofthe tongue, multiple endocrine neoplasia syndrome, mycosis fungoides,myelodysplastic syndromes, myelodysplastic/myeloproliferative diseases,chronic myelogenous leukemia, acute myeloid leukemia, multiple myeloma,chronic myeloproliferative disorders, nasopharyngeal cancer,neuroblastoma, oral cancer, oral cavity cancer, oropharyngeal cancer,ovarian cancer, ovarian epithelial cancer, ovarian low malignantpotential tumor, pancreatic cancer, islet cell pancreatic cancer,paranasal sinus and nasal cavity cancer, parathyroid cancer, penilecancer, pharyngeal cancer, pheochromocytoma, pineoblastoma andsupratentorial primitive neuroectodermal tumors, pituitary tumor, plasmacell neoplasm/multiple myeloma, pleuropulmonary blastoma, prostatecancer, rectal cancer, renal pelvis and ureter, transitional cellcancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, ewingfamily of sarcoma tumors, Kaposi Sarcoma, soft tissue sarcoma, uterinecancer, uterine sarcoma, skin cancer (non-melanoma), skin cancer(melanoma), merkel cell skin carcinoma, small intestine cancer, softtissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer,supratentorial primitive neuroectodermal tumors, testicular cancer,throat cancer, thymoma, thymoma and thymic carcinoma, thyroid cancer,transitional cell cancer of the renal pelvis and ureter and otherurinary organs, gestational trophoblastic tumor, urethral cancer,endometrial uterine cancer, uterine sarcoma, uterine corpus cancer,vaginal cancer, vulvar cancer, and Wilm's Tumor.

A “cell proliferative disorder of the hematologic system” is a cellproliferative disorder involving cells of the hematologic system. A cellproliferative disorder of the hematologic system can include lymphoma,leukemia, myeloid neoplasms, mast cell neoplasms, myelodysplasia, benignmonoclonal gammopathy, lymphomatoid granulomatosis, lymphomatoidpapulosis, polycythemia vera, chronic myelocytic leukemia, agnogenicmyeloid metaplasia, and essential thrombocythemia. A cell proliferativedisorder of the hematologic system can include hyperplasia, dysplasia,and metaplasia of cells of the hematologic system. Preferably,compositions of the present invention may be used to treat a cancerselected from the group consisting of a hematologic cancer of thepresent invention or a hematologic cell proliferative disorder of thepresent invention. A hematologic cancer of the present invention caninclude multiple myeloma, lymphoma (including Hodgkin's lymphoma,non-Hodgkin's lymphoma, childhood lymphomas, and lymphomas oflymphocytic and cutaneous origin), leukemia (including childhoodleukemia, hairy-cell leukemia, acute lymphocytic leukemia, acutemyelocytic leukemia, chronic lymphocytic leukemia, chronic myelocyticleukemia, chronic myelogenous leukemia, and mast cell leukemia), myeloidneoplasms and mast cell neoplasms.

A “cell proliferative disorder of the lung” is a cell proliferativedisorder involving cells of the lung. Cell proliferative disorders ofthe lung can include all forms of cell proliferative disorders affectinglung cells. Cell proliferative disorders of the lung can include lungcancer, a precancer or precancerous condition of the lung, benigngrowths or lesions of the lung, and malignant growths or lesions of thelung, and metastatic lesions in tissue and organs in the body other thanthe lung. Preferably, compositions of the present invention may be usedto treat lung cancer or cell proliferative disorders of the lung. Lungcancer can include all forms of cancer of the lung. Lung cancer caninclude malignant lung neoplasms, carcinoma in situ, typical carcinoidtumors, and atypical carcinoid tumors. Lung cancer can include smallcell lung cancer (“SCLC”), non-small cell lung cancer (“NSCLC”),squamous cell carcinoma, adenocarcinoma, small cell carcinoma, largecell carcinoma, adenosquamous cell carcinoma, and mesothelioma. Lungcancer can include “scar carcinoma”, bronchioalveolar carcinoma, giantcell carcinoma, spindle cell carcinoma, and large cell neuroendocrinecarcinoma. Lung cancer can include lung neoplasms having histologic andultrastructual heterogeneity (e.g., mixed cell types).

Cell proliferative disorders of the lung can include all forms of cellproliferative disorders affecting lung cells. Cell proliferativedisorders of the lung can include lung cancer, precancerous conditionsof the lung. Cell proliferative disorders of the lung can includehyperplasia, metaplasia, and dysplasia of the lung. Cell proliferativedisorders of the lung can include asbestos-induced hyperplasia, squamousmetaplasia, and benign reactive mesothelial metaplasia. Cellproliferative disorders of the lung can include replacement of columnarepithelium with stratified squamous epithelium, and mucosal dysplasia.Individuals exposed to inhaled injurious environmental agents such ascigarette smoke and asbestos may be at increased risk for developingcell proliferative disorders of the lung. Prior lung diseases that maypredispose individuals to development of cell proliferative disorders ofthe lung can include chronic interstitial lung disease, necrotizingpulmonary disease, scleroderma, rheumatoid disease, sarcoidosis,interstitial pneumonitis, tuberculosis, repeated pneumonias, idiopathicpulmonary fibrosis, granulomata, asbestosis, fibrosing alveolitis, andHodgkin's disease.

A “cell proliferative disorder of the colon” is a cell proliferativedisorder involving cells of the colon. Preferably, the cellproliferative disorder of the colon is colon cancer. Preferably,compositions of the present invention may be used to treat colon canceror cell proliferative disorders of the colon. Colon cancer can includeall forms of cancer of the colon. Colon cancer can include sporadic andhereditary colon cancers. Colon cancer can include malignant colonneoplasms, carcinoma in situ, typical carcinoid tumors, and atypicalcarcinoid tumors. Colon cancer can include adenocarcinoma, squamous cellcarcinoma, and adenosquamous cell carcinoma. Colon cancer can beassociated with a hereditary syndrome selected from the group consistingof hereditary nonpolyposis colorectal cancer, familial adenomatouspolyposis, Gardner's syndrome, Peutz-Jeghers syndrome, Turcot's syndromeand juvenile polyposis. Colon cancer can be caused by a hereditarysyndrome selected from the group consisting of hereditary nonpolyposiscolorectal cancer, familial adenomatous polyposis, Gardner's syndrome,Peutz-Jeghers syndrome, Turcot's syndrome and juvenile polyposis.

Cell proliferative disorders of the colon can include all forms of cellproliferative disorders affecting colon cells. Cell proliferativedisorders of the colon can include colon cancer, precancerous conditionsof the colon, adenomatous polyps of the colon and metachronous lesionsof the colon. A cell proliferative disorder of the colon can includeadenoma. Cell proliferative disorders of the colon can be characterizedby hyperplasia, metaplasia, and dysplasia of the colon. Prior colondiseases that may predispose individuals to development of cellproliferative disorders of the colon can include prior colon cancer.Current disease that may predispose individuals to development of cellproliferative disorders of the colon can include Crohn's disease andulcerative colitis. A cell proliferative disorder of the colon can beassociated with a mutation in a gene selected from the group consistingof p53, ras, FAP and DCC. An individual can have an elevated risk ofdeveloping a cell proliferative disorder of the colon due to thepresence of a mutation in a gene selected from the group consisting ofp53, ras, FAP and DCC.

A “cell proliferative disorder of the pancreas” is a cell proliferativedisorder involving cells of the pancreas. Cell proliferative disordersof the pancreas can include all forms of cell proliferative disordersaffecting pancreatic cells. Cell proliferative disorders of the pancreascan include pancreas cancer, a precancer or precancerous condition ofthe pancreas, hyperplasia of the pancreas, and dysaplasia of thepancreas, benign growths or lesions of the pancreas, and malignantgrowths or lesions of the pancreas, and metastatic lesions in tissue andorgans in the body other than the pancreas. Pancreatic cancer includesall forms of cancer of the pancreas. Pancreatic cancer can includeductal adenocarcinoma, adenosquamous carcinoma, pleomorphic giant cellcarcinoma, mucinous adenocarcinoma, osteoclast-like giant cellcarcinoma, mucinous cystadenocarcinoma, acinar carcinoma, unclassifiedlarge cell carcinoma, small cell carcinoma, pancreatoblastoma, papillaryneoplasm, mucinous cystadenoma, papillary cystic neoplasm, and serouscystadenoma. Pancreatic cancer can also include pancreatic neoplasmshaving histologic and ultrastructual heterogeneity (e.g., mixed celltypes).

A “cell proliferative disorder of the prostate” is a cell proliferativedisorder involving cells of the prostate. Cell proliferative disordersof the prostate can include all forms of cell proliferative disordersaffecting prostate cells. Cell proliferative disorders of the prostatecan include prostate cancer, a precancer or precancerous condition ofthe prostate, benign growths or lesions of the prostate, and malignantgrowths or lesions of the prostate, and metastatic lesions in tissue andorgans in the body other than the prostate. Cell proliferative disordersof the prostate can include hyperplasia, metaplasia, and dysplasia ofthe prostate.

A “cell proliferative disorder of the skin” is a cell proliferativedisorder involving cells of the skin. Cell proliferative disorders ofthe skin can include all forms of cell proliferative disorders affectingskin cells. Cell proliferative disorders of the skin can include aprecancer or precancerous condition of the skin, benign growths orlesions of the skin, melanoma, malignant melanoma and other malignantgrowths or lesions of the skin, and metastatic lesions in tissue andorgans in the body other than the skin. Cell proliferative disorders ofthe skin can include hyperplasia, metaplasia, and dysplasia of the skin.

A “cell proliferative disorder of the ovary” is a cell proliferativedisorder involving cells of the ovary. Cell proliferative disorders ofthe ovary can include all forms of cell proliferative disordersaffecting cells of the ovary. Cell proliferative disorders of the ovarycan include a precancer or precancerous condition of the ovary, benigngrowths or lesions of the ovary, ovarian cancer, malignant growths orlesions of the ovary, and metastatic lesions in tissue and organs in thebody other than the ovary. Cell proliferative disorders of the skin caninclude hyperplasia, metaplasia, and dysplasia of cells of the ovary.

A “cell proliferative disorder of the breast” is a cell proliferativedisorder involving cells of the breast. Cell proliferative disorders ofthe breast can include all forms of cell proliferative disordersaffecting breast cells. Cell proliferative disorders of the breast caninclude breast cancer, a precancer or precancerous condition of thebreast, benign growths or lesions of the breast, and malignant growthsor lesions of the breast, and metastatic lesions in tissue and organs inthe body other than the breast. Cell proliferative disorders of thebreast can include hyperplasia, metaplasia, and dysplasia of the breast.

A cell proliferative disorder of the breast can be a precancerouscondition of the breast. Compositions of the present invention may beused to treat a precancerous condition of the breast. A precancerouscondition of the breast can include atypical hyperplasia of the breast,ductal carcinoma in situ (DCIS), intraductal carcinoma, lobularcarcinoma in situ (LCIS), lobular neoplasia, and stage 0 or grade 0growth or lesion of the breast (e.g., stage 0 or grade 0 breast cancer,or carcinoma in situ). A precancerous condition of the breast can bestaged according to the TNM classification scheme as accepted by theAmerican Joint Committee on Cancer (AJCC), where the primary tumor (T)has been assigned a stage of T0 or Tis; and where the regional lymphnodes (N) have been assigned a stage of N0; and where distant metastasis(M) has been assigned a stage of M0.

The cell proliferative disorder of the breast can be breast cancer.Preferably, compositions of the present invention may be used to treatbreast cancer. Breast cancer includes all forms of cancer of the breast.Breast cancer can include primary epithelial breast cancers. Breastcancer can include cancers in which the breast is involved by othertumors such as lymphoma, sarcoma or melanoma. Breast cancer can includecarcinoma of the breast, ductal carcinoma of the breast, lobularcarcinoma of the breast, undifferentiated carcinoma of the breast,cystosarcoma phyllodes of the breast, angiosarcoma of the breast, andprimary lymphoma of the breast. Breast cancer can include Stage I, II,IIIA, IIIB, IIIC and IV breast cancer. Ductal carcinoma of the breastcan include invasive carcinoma, invasive carcinoma in situ withpredominant intraductal component, inflammatory breast cancer, and aductal carcinoma of the breast with a histologic type selected from thegroup consisting of comedo, mucinous (colloid), medullary, medullarywith lymphcytic infiltrate, papillary, scirrhous, and tubular. Lobularcarcinoma of the breast can include invasive lobular carcinoma withpredominant in situ component, invasive lobular carcinoma, andinfiltrating lobular carcinoma. Breast cancer can include Paget'sdisease, Paget's disease with intraductal carcinoma, and Paget's diseasewith invasive ductal carcinoma. Breast cancer can include breastneoplasms having histologic and ultrastructual heterogeneity (e.g.,mixed cell types).

Preferably, compound of the present invention, or a pharmaceuticallyacceptable salt, prodrug, metabolite, polymorph or solvate thereof, maybe used to treat breast cancer. A breast cancer that is to be treatedcan include familial breast cancer. A breast cancer that is to betreated can include sporadic breast cancer. A breast cancer that is tobe treated can arise in a male subject. A breast cancer that is to betreated can arise in a female subject. A breast cancer that is to betreated can arise in a premenopausal female subject or a postmenopausalfemale subject. A breast cancer that is to be treated can arise in asubject equal to or older than 30 years old, or a subject younger than30 years old. A breast cancer that is to be treated has arisen in asubject equal to or older than 50 years old, or a subject younger than50 years old. A breast cancer that is to be treated can arise in asubject equal to or older than 70 years old, or a subject younger than70 years old.

A breast cancer that is to be treated can be typed to identify afamilial or spontaneous mutation in BRCA1, BRCA2, or p53. A breastcancer that is to be treated can be typed as having a HER2/neu geneamplification, as overexpressing HER2/neu, or as having a low,intermediate or high level of HER2/neu expression. A breast cancer thatis to be treated can be typed for a marker selected from the groupconsisting of estrogen receptor (ER), progesterone receptor (PR), humanepidermal growth factor receptor-2, Ki-67, CA15-3, CA 27-29, and c-Met.A breast cancer that is to be treated can be typed as ER-unknown,ER-rich or ER-poor. A breast cancer that is to be treated can be typedas ER-negative or ER-positive. ER-typing of a breast cancer may beperformed by any reproducible means. ER-typing of a breast cancer may beperformed as set forth in Onkologie 27: 175-179 (2004). A breast cancerthat is to be treated can be typed as PR-unknown, PR-rich or PR-poor. Abreast cancer that is to be treated can be typed as PR-negative orPR-positive. A breast cancer that is to be treated can be typed asreceptor positive or receptor negative. A breast cancer that is to betreated can be typed as being associated with elevated blood levels ofCA 15-3, or CA 27-29, or both.

A breast cancer that is to be treated can include a localized tumor ofthe breast. A breast cancer that is to be treated can include a tumor ofthe breast that is associated with a negative sentinel lymph node (SLN)biopsy. A breast cancer that is to be treated can include a tumor of thebreast that is associated with a positive sentinel lymph node (SLN)biopsy. A breast cancer that is to be treated can include a tumor of thebreast that is associated with one or more positive axillary lymphnodes, where the axillary lymph nodes have been staged by any applicablemethod. A breast cancer that is to be treated can include a tumor of thebreast that has been typed as having nodal negative status (e.g.,node-negative) or nodal positive status (e.g., node-positive). A breastcancer that is to be treated can include a tumor of the breast that hasmetastasized to other locations in the body. A breast cancer that is tobe treated can be classified as having metastasized to a locationselected from the group consisting of bone, lung, liver, or brain. Abreast cancer that is to be treated can be classified according to acharacteristic selected from the group consisting of metastatic,localized, regional, local-regional, locally advanced, distant,multicentric, bilateral, ipsilateral, contralateral, newly diagnosed,recurrent, and inoperable.

A compound of the present invention, or a pharmaceutically acceptablesalt, prodrug, metabolite, polymorph or solvate thereof, may be used totreat or prevent a cell proliferative disorder of the breast, or totreat or prevent breast cancer, in a subject having an increased risk ofdeveloping breast cancer relative to the population at large. A subjectwith an increased risk of developing breast cancer relative to thepopulation at large is a female subject with a family history orpersonal history of breast cancer. A subject with an increased risk ofdeveloping breast cancer relative to the population at large is a femalesubject having a germ-line or spontaneous mutation in BRCA1 or BRCA2, orboth. A subject with an increased risk of developing breast cancerrelative to the population at large is a female subject with a familyhistory of breast cancer and a germ-line or spontaneous mutation inBRCA1 or BRCA2, or both. A subject with an increased risk of developingbreast cancer relative to the population at large is a female who isgreater than 30 years old, greater than 40 years old, greater than 50years old, greater than 60 years old, greater than 70 years old, greaterthan 80 years old, or greater than 90 years old. A subject with anincreased risk of developing breast cancer relative to the population atlarge is a subject with atypical hyperplasia of the breast, ductalcarcinoma in situ (DCIS), intraductal carcinoma, lobular carcinoma insitu (LCIS), lobular neoplasia, or a stage 0 growth or lesion of thebreast (e.g., stage 0 or grade 0 breast cancer, or carcinoma in situ).

A breast cancer that is to be treated can histologically gradedaccording to the Scarff-Bloom-Richardson system, wherein a breast tumorhas been assigned a mitosis count score of 1, 2, or 3; a nuclearpleiomorphism score of 1, 2, or 3; a tubule formation score of 1, 2, or3; and a total Scarff-Bloom-Richardson score of between 3 and 9. Abreast cancer that is to be treated can be assigned a tumor gradeaccording to the International Consensus Panel on the Treatment ofBreast Cancer selected from the group consisting of grade 1, grade 1-2,grade 2, grade 2-3, or grade 3.

A cancer that is to be treated can be staged according to the AmericanJoint Committee on Cancer (AJCC) TNM classification system, where thetumor (T) has been assigned a stage of TX, T1, T1mic, T1 a, T1 b, T1 c,T2, T3, T4, T4 a, T4 b, T4 c, or T4 d; and where the regional lymphnodes (N) have been assigned a stage of NX, N0, N1, N2, N2 a, N2 b, N3,N3 a, N3 b, or N3 c; and where distant metastasis (M) can be assigned astage of MX, M0, or M1. A cancer that is to be treated can be stagedaccording to an American Joint Committee on Cancer (AJCC) classificationas Stage I, Stage IIA, Stage IIB, Stage IIIA, Stage IIIB, Stage IIIC, orStage IV. A cancer that is to be treated can be assigned a gradeaccording to an AJCC classification as Grade GX (e.g., grade cannot beassessed), Grade 1, Grade 2, Grade 3 or Grade 4. A cancer that is to betreated can be staged according to an AJCC pathologic classification(pN) of pNX, pN0, PN0 (I−), PN0 (I+), PNO (mol−), PN0 (mol+), PN1,PN1(mi), PN1 a, PN1 b, PN1 c, pN2, pN2 a, pN2 b, pN3, pN3 a, pN3 b, orpN3 c.

A cancer that is to be treated can include a tumor that has beendetermined to be less than or equal to about 2 centimeters in diameter.A cancer that is to be treated can include a tumor that has beendetermined to be from about 2 to about 5 centimeters in diameter. Acancer that is to be treated can include a tumor that has beendetermined to be greater than or equal to about 3 centimeters indiameter. A cancer that is to be treated can include a tumor that hasbeen determined to be greater than 5 centimeters in diameter. A cancerthat is to be treated can be classified by microscopic appearance aswell differentiated, moderately differentiated, poorly differentiated,or undifferentiated. A cancer that is to be treated can be classified bymicroscopic appearance with respect to mitosis count (e.g., amount ofcell division) or nuclear pleiomorphism (e.g., change in cells). Acancer that is to be treated can be classified by microscopic appearanceas being associated with areas of necrosis (e.g., areas of dying ordegenerating cells). A cancer that is to be treated can be classified ashaving an abnormal karyotype, having an abnormal number of chromosomes,or having one or more chromosomes that are abnormal in appearance. Acancer that is to be treated can be classified as being aneuploid,triploid, tetraploid, or as having an altered ploidy. A cancer that isto be treated can be classified as having a chromosomal translocation,or a deletion or duplication of an entire chromosome, or a region ofdeletion, duplication or amplification of a portion of a chromosome.

A cancer that is to be treated can be evaluated by DNA cytometry, flowcytometry, or image cytometry. A cancer that is to be treated can betyped as having 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of cellsin the synthesis stage of cell division (e.g., in S phase of celldivision). A cancer that is to be treated can be typed as having a lowS-phase fraction or a high S-phase fraction.

As used herein, a “normal cell” is a cell that cannot be classified aspart of a “cell proliferative disorder”. A normal cell lacks unregulatedor abnormal growth, or both, that can lead to the development of anunwanted condition or disease. Preferably, a normal cell possessesnormally functioning cell cycle checkpoint control mechanisms.

As used herein, “contacting a cell” refers to a condition in which acompound or other composition of matter is in direct contact with acell, or is close enough to induce a desired biological effect in acell.

As used herein, “candidate compound” refers to a compound of the presentinvention, or a pharmaceutically acceptable salt, prodrug, metabolite,polymorph or solvate thereof, that has been or will be tested in one ormore in vitro or in vivo biological assays, in order to determine ifthat compound is likely to elicit a desired biological or medicalresponse in a cell, tissue, system, animal or human that is being soughtby a researcher or clinician. A candidate compound is a compound of thepresent invention, or a pharmaceutically acceptable salt, prodrug,metabolite, polymorph or solvate thereof. The biological or medicalresponse can be the treatment of cancer. The biological or medicalresponse can be treatment or prevention of a cell proliferativedisorder. In vitro or in vivo biological assays can include, but are notlimited to, enzymatic activity assays, electrophoretic mobility shiftassays, reporter gene assays, in vitro cell viability assays, and theassays described herein.

As used herein, “monotherapy” refers to the administration of a singleactive or therapeutic compound to a subject in need thereof. Preferably,monotherapy will involve administration of a therapeutically effectiveamount of an active compound. For example, cancer monotherapy with oneof the compound of the present invention, or a pharmaceuticallyacceptable salt, prodrug, metabolite, analog or derivative thereof, to asubject in need of treatment of cancer. Monotherapy may be contrastedwith combination therapy, in which a combination of multiple activecompounds is administered, preferably with each component of thecombination present in a therapeutically effective amount. In oneaspect, monotherapy with a compound of the present invention, or apharmaceutically acceptable salt, prodrug, metabolite, polymorph orsolvate thereof, is more effective than combination therapy in inducinga desired biological effect.

As used herein, “treating” or “treat” describes the management and careof a patient for the purpose of combating a disease, condition, ordisorder and includes the administration of a compound of the presentinvention, or a pharmaceutically acceptable salt, prodrug, metabolite,polymorph or solvate thereof, to alleviate the symptoms or complicationsof a disease, condition or disorder, or to eliminate the disease,condition or disorder.

A compound of the present invention, or a pharmaceutically acceptablesalt, prodrug, metabolite, polymorph or solvate thereof, can also beused to prevent a disease, condition or disorder. As used herein,“preventing” or “prevent” describes reducing or eliminating the onset ofthe symptoms or complications of the disease, condition or disorder.

As used herein, the term “alleviate” is meant to describe a process bywhich the severity of a sign or symptom of a disorder is decreased.Importantly, a sign or symptom can be alleviated without beingeliminated. In a preferred embodiment, the administration ofpharmaceutical compositions of the invention leads to the elimination ofa sign or symptom, however, elimination is not required. Effectivedosages are expected to decrease the severity of a sign or symptom. Forinstance, a sign or symptom of a disorder such as cancer, which canoccur in multiple locations, is alleviated if the severity of the canceris decreased within at least one of multiple locations.

As used herein, the term “severity” is meant to describe the potentialof cancer to transform from a precancerous, or benign, state into amalignant state. Alternatively, or in addition, severity is meant todescribe a cancer stage, for example, according to the TNM system(accepted by the International Union Against Cancer (UICC) and theAmerican Joint Committee on Cancer (AJCC)) or by other art-recognizedmethods. Cancer stage refers to the extent or severity of the cancer,based on factors such as the location of the primary tumor, tumor size,number of tumors, and lymph node involvement (spread of cancer intolymph nodes). Alternatively, or in addition, severity is meant todescribe the tumor grade by art-recognized methods (see, National CancerInstitute, www.cancer.gov). Tumor grade is a system used to classifycancer cells in terms of how abnormal they look under a microscope andhow quickly the tumor is likely to grow and spread. Many factors areconsidered when determining tumor grade, including the structure andgrowth pattern of the cells. The specific factors used to determinetumor grade vary with each type of cancer. Severity also describes ahistologic grade, also called differentiation, which refers to how muchthe tumor cells resemble normal cells of the same tissue type (see,National Cancer Institute, www.cancer.gov). Furthermore, severitydescribes a nuclear grade, which refers to the size and shape of thenucleus in tumor cells and the percentage of tumor cells that aredividing (see, National Cancer Institute, www.cancer.gov).

In another aspect of the invention, severity describes the degree towhich a tumor has secreted growth factors, degraded the extracellularmatrix, become vascularized, lost adhesion to juxtaposed tissues, ormetastasized. Moreover, severity describes the number of locations towhich a primary tumor has metastasized. Finally, severity includes thedifficulty of treating tumors of varying types and locations. Forexample, inoperable tumors, those cancers which have greater access tomultiple body systems (hematological and immunological tumors), andthose which are the most resistant to traditional treatments areconsidered most severe. In these situations, prolonging the lifeexpectancy of the subject and/or reducing pain, decreasing theproportion of cancerous cells or restricting cells to one system, andimproving cancer stage/tumor grade/histological grade/nuclear grade areconsidered alleviating a sign or symptom of the cancer.

As used herein the term “symptom” is defined as an indication ofdisease, illness, injury, or that something is not right in the body.Symptoms are felt or noticed by the individual experiencing the symptom,but may not easily be noticed by others. Others are defined asnon-health-care professionals.

As used herein the term “sign” is also defined as an indication thatsomething is not right in the body. But signs are defined as things thatcan be seen by a doctor, nurse, or other health care professional.

Cancer is a group of diseases that may cause almost any sign or symptom.The signs and symptoms will depend on where the cancer is, the size ofthe cancer, and how much it affects the nearby organs or structures. Ifa cancer spreads (metastasizes), then symptoms may appear in differentparts of the body.

As a cancer grows, it begins to push on nearby organs, blood vessels,and nerves. This pressure creates some of the signs and symptoms ofcancer. If the cancer is in a critical area, such as certain parts ofthe brain, even the smallest tumor can cause early symptoms.

But sometimes cancers start in places where it does not cause anysymptoms until the cancer has grown quite large. Pancreas cancers, forexample, do not usually grow large enough to be felt from the outside ofthe body. Some pancreatic cancers do not cause symptoms until they beginto grow around nearby nerves (this causes a backache). Others growaround the bile duct, which blocks the flow of bile and leads to ayellowing of the skin known as jaundice. By the time a pancreatic cancercauses these signs or symptoms, it has usually reached an advancedstage.

A cancer may also cause symptoms such as fever, fatigue, or weight loss.This may be because cancer cells use up much of the body's energy supplyor release substances that change the body's metabolism. Or the cancermay cause the immune system to react in ways that produce thesesymptoms.

Sometimes, cancer cells release substances into the bloodstream thatcause symptoms not usually thought to result from cancers. For example,some cancers of the pancreas can release substances which cause bloodclots to develop in veins of the legs. Some lung cancers makehormone-like substances that affect blood calcium levels, affectingnerves and muscles and causing weakness and dizziness

Cancer presents several general signs or symptoms that occur when avariety of subtypes of cancer cells are present. Most people with cancerwill lose weight at some time with their disease. An unexplained(unintentional) weight loss of 10 pounds or more may be the first signof cancer, particularly cancers of the pancreas, stomach, esophagus, orlung.

Fever is very common with cancer, but is more often seen in advanceddisease. Almost all patients with cancer will have fever at some time,especially if the cancer or its treatment affects the immune system andmakes it harder for the body to fight infection. Less often, fever maybe an early sign of cancer, such as with leukemia or lymphoma.

Fatigue may be an important symptom as cancer progresses. It may happenearly, though, in cancers such as with leukemia, or if the cancer iscausing an ongoing loss of blood, as in some colon or stomach cancers.

Pain may be an early symptom with some cancers such as bone cancers ortesticular cancer. But most often pain is a symptom of advanced disease.

Along with cancers of the skin (see next section), some internal cancerscan cause skin signs that can be seen. These changes include the skinlooking darker (hyperpigmentation), yellow (jaundice), or red(erythema); itching; or excessive hair growth.

Alternatively, or in addition, cancer subtypes present specific signs orsymptoms. Changes in bowel habits or bladder function could indicatecancer. Long-term constipation, diarrhea, or a change in the size of thestool may be a sign of colon cancer. Pain with urination, blood in theurine, or a change in bladder function (such as more frequent or lessfrequent urination) could be related to bladder or prostate cancer.

Changes in skin condition or appearance of a new skin condition couldindicate cancer. Skin cancers may bleed and look like sores that do notheal. A long-lasting sore in the mouth could be an oral cancer,especially in patients who smoke, chew tobacco, or frequently drinkalcohol. Sores on the penis or vagina may either be signs of infectionor an early cancer.

Unusual bleeding or discharge could indicate cancer. Unusual bleedingcan happen in either early or advanced cancer. Blood in the sputum(phlegm) may be a sign of lung cancer. Blood in the stool (or a dark orblack stool) could be a sign of colon or rectal cancer. Cancer of thecervix or the endometrium (lining of the uterus) can cause vaginalbleeding. Blood in the urine may be a sign of bladder or kidney cancer.A bloody discharge from the nipple may be a sign of breast cancer.

A thickening or lump in the breast or in other parts of the body couldindicate the presence of a cancer. Many cancers can be felt through theskin, mostly in the breast, testicle, lymph nodes (glands), and the softtissues of the body. A lump or thickening may be an early or late signof cancer. Any lump or thickening could be indicative of cancer,especially if the formation is new or has grown in size.

Indigestion or trouble swallowing could indicate cancer. While thesesymptoms commonly have other causes, indigestion or swallowing problemsmay be a sign of cancer of the esophagus, stomach, or pharynx (throat).

Recent changes in a wart or mole could be indicative of cancer. Anywart, mole, or freckle that changes in color, size, or shape, or losesits definite borders indicates the potential development of cancer. Forexample, the skin lesion may be a melanoma.

A persistent cough or hoarseness could be indicative of cancer. A coughthat does not go away may be a sign of lung cancer. Hoarseness can be asign of cancer of the larynx (voice box) or thyroid.

While the signs and symptoms listed above are the more common ones seenwith cancer, there are many others that are less common and are notlisted here. However, all art-recognized signs and symptoms of cancerare contemplated and encompassed by the instant invention.

Treating cancer can result in a reduction in size of a tumor. Areduction in size of a tumor may also be referred to as “tumorregression”. Preferably, after treatment, tumor size is reduced by 5% orgreater relative to its size prior to treatment; more preferably, tumorsize is reduced by 10% or greater; more preferably, reduced by 20% orgreater; more preferably, reduced by 30% or greater; more preferably,reduced by 40% or greater; even more preferably, reduced by 50% orgreater; and most preferably, reduced by greater than 75% or greater.Size of a tumor may be measured by any reproducible means ofmeasurement. The size of a tumor may be measured as a diameter of thetumor.

Treating cancer can result in a reduction in tumor volume. Preferably,after treatment, tumor volume is reduced by 5% or greater relative toits size prior to treatment; more preferably, tumor volume is reduced by10% or greater; more preferably, reduced by 20% or greater; morepreferably, reduced by 30% or greater; more preferably, reduced by 40%or greater; even more preferably, reduced by 50% or greater; and mostpreferably, reduced by greater than 75% or greater. Tumor volume may bemeasured by any reproducible means of measurement.

Treating cancer results in a decrease in number of tumors. Preferably,after treatment, tumor number is reduced by 5% or greater relative tonumber prior to treatment; more preferably, tumor number is reduced by10% or greater; more preferably, reduced by 20% or greater; morepreferably, reduced by 30% or greater; more preferably, reduced by 40%or greater; even more preferably, reduced by 50% or greater; and mostpreferably, reduced by greater than 75%. Number of tumors may bemeasured by any reproducible means of measurement. The number of tumorsmay be measured by counting tumors visible to the naked eye or at aspecified magnification. Preferably, the specified magnification is 2×,3×, 4×, 5×, 10×, or 50×.

Treating cancer can result in a decrease in number of metastatic lesionsin other tissues or organs distant from the primary tumor site.Preferably, after treatment, the number of metastatic lesions is reducedby 5% or greater relative to number prior to treatment; more preferably,the number of metastatic lesions is reduced by 10% or greater; morepreferably, reduced by 20% or greater; more preferably, reduced by 30%or greater; more preferably, reduced by 40% or greater; even morepreferably, reduced by 50% or greater; and most preferably, reduced bygreater than 75%. The number of metastatic lesions may be measured byany reproducible means of measurement. The number of metastatic lesionsmay be measured by counting metastatic lesions visible to the naked eyeor at a specified magnification. Preferably, the specified magnificationis 2×, 3×, 4×, 5×, 10×, or 50×.

Treating cancer can result in an increase in average survival time of apopulation of treated subjects in comparison to a population receivingcarrier alone. Preferably, the average survival time is increased bymore than 30 days; more preferably, by more than 60 days; morepreferably, by more than 90 days; and most preferably, by more than 120days. An increase in average survival time of a population may bemeasured by any reproducible means. An increase in average survival timeof a population may be measured, for example, by calculating for apopulation the average length of survival following initiation oftreatment with an active compound. An increase in average survival timeof a population may also be measured, for example, by calculating for apopulation the average length of survival following completion of afirst round of treatment with an active compound.

Treating cancer can result in an increase in average survival time of apopulation of treated subjects in comparison to a population ofuntreated subjects. Preferably, the average survival time is increasedby more than 30 days; more preferably, by more than 60 days; morepreferably, by more than 90 days; and most preferably, by more than 120days. An increase in average survival time of a population may bemeasured by any reproducible means. An increase in average survival timeof a population may be measured, for example, by calculating for apopulation the average length of survival following initiation oftreatment with an active compound. An increase in average survival timeof a population may also be measured, for example, by calculating for apopulation the average length of survival following completion of afirst round of treatment with an active compound.

Treating cancer can result in increase in average survival time of apopulation of treated subjects in comparison to a population receivingmonotherapy with a drug that is not a compound of the present invention,or a pharmaceutically acceptable salt, prodrug, metabolite, analog orderivative thereof. Preferably, the average survival time is increasedby more than 30 days; more preferably, by more than 60 days; morepreferably, by more than 90 days; and most preferably, by more than 120days. An increase in average survival time of a population may bemeasured by any reproducible means. An increase in average survival timeof a population may be measured, for example, by calculating for apopulation the average length of survival following initiation oftreatment with an active compound. An increase in average survival timeof a population may also be measured, for example, by calculating for apopulation the average length of survival following completion of afirst round of treatment with an active compound.

Treating cancer can result in a decrease in the mortality rate of apopulation of treated subjects in comparison to a population receivingcarrier alone. Treating cancer can result in a decrease in the mortalityrate of a population of treated subjects in comparison to an untreatedpopulation. Treating cancer can result in a decrease in the mortalityrate of a population of treated subjects in comparison to a populationreceiving monotherapy with a drug that is not a compound of the presentinvention, or a pharmaceutically acceptable salt, prodrug, metabolite,analog or derivative thereof. Preferably, the mortality rate isdecreased by more than 2%; more preferably, by more than 5%; morepreferably, by more than 10%; and most preferably, by more than 25%. Adecrease in the mortality rate of a population of treated subjects maybe measured by any reproducible means. A decrease in the mortality rateof a population may be measured, for example, by calculating for apopulation the average number of disease-related deaths per unit timefollowing initiation of treatment with an active compound. A decrease inthe mortality rate of a population may also be measured, for example, bycalculating for a population the average number of disease-relateddeaths per unit time following completion of a first round of treatmentwith an active compound.

Treating cancer can result in a decrease in tumor growth rate.Preferably, after treatment, tumor growth rate is reduced by at least 5%relative to number prior to treatment; more preferably, tumor growthrate is reduced by at least 10%; more preferably, reduced by at least20%; more preferably, reduced by at least 30%; more preferably, reducedby at least 40%; more preferably, reduced by at least 50%; even morepreferably, reduced by at least 50%; and most preferably, reduced by atleast 75%. Tumor growth rate may be measured by any reproducible meansof measurement. Tumor growth rate can be measured according to a changein tumor diameter per unit time.

Treating cancer can result in a decrease in tumor regrowth. Preferably,after treatment, tumor regrowth is less than 5%; more preferably, tumorregrowth is less than 10%; more preferably, less than 20%; morepreferably, less than 30%; more preferably, less than 40%; morepreferably, less than 50%; even more preferably, less than 50%; and mostpreferably, less than 75%. Tumor regrowth may be measured by anyreproducible means of measurement. Tumor regrowth is measured, forexample, by measuring an increase in the diameter of a tumor after aprior tumor shrinkage that followed treatment. A decrease in tumorregrowth is indicated by failure of tumors to reoccur after treatmenthas stopped.

Treating or preventing a cell proliferative disorder can result in areduction in the rate of cellular proliferation. Preferably, aftertreatment, the rate of cellular proliferation is reduced by at least 5%;more preferably, by at least 10%; more preferably, by at least 20%; morepreferably, by at least 30%; more preferably, by at least 40%; morepreferably, by at least 50%; even more preferably, by at least 50%; andmost preferably, by at least 75%. The rate of cellular proliferation maybe measured by any reproducible means of measurement. The rate ofcellular proliferation is measured, for example, by measuring the numberof dividing cells in a tissue sample per unit time.

Treating or preventing a cell proliferative disorder can result in areduction in the proportion of proliferating cells. Preferably, aftertreatment, the proportion of proliferating cells is reduced by at least5%; more preferably, by at least 10%; more preferably, by at least 20%;more preferably, by at least 30%; more preferably, by at least 40%; morepreferably, by at least 50%; even more preferably, by at least 50%; andmost preferably, by at least 75%. The proportion of proliferating cellsmay be measured by any reproducible means of measurement. Preferably,the proportion of proliferating cells is measured, for example, byquantifying the number of dividing cells relative to the number ofnondividing cells in a tissue sample. The proportion of proliferatingcells can be equivalent to the mitotic index.

Treating or preventing a cell proliferative disorder can result in adecrease in size of an area or zone of cellular proliferation.Preferably, after treatment, size of an area or zone of cellularproliferation is reduced by at least 5% relative to its size prior totreatment; more preferably, reduced by at least 10%; more preferably,reduced by at least 20%; more preferably, reduced by at least 30%; morepreferably, reduced by at least 40%; more preferably, reduced by atleast 50%; even more preferably, reduced by at least 50%; and mostpreferably, reduced by at least 75%. Size of an area or zone of cellularproliferation may be measured by any reproducible means of measurement.The size of an area or zone of cellular proliferation may be measured asa diameter or width of an area or zone of cellular proliferation.

Treating or preventing a cell proliferative disorder can result in adecrease in the number or proportion of cells having an abnormalappearance or morphology. Preferably, after treatment, the number ofcells having an abnormal morphology is reduced by at least 5% relativeto its size prior to treatment; more preferably, reduced by at least10%; more preferably, reduced by at least 20%; more preferably, reducedby at least 30%; more preferably, reduced by at least 40%; morepreferably, reduced by at least 50%; even more preferably, reduced by atleast 50%; and most preferably, reduced by at least 75%. An abnormalcellular appearance or morphology may be measured by any reproduciblemeans of measurement. An abnormal cellular morphology can be measured bymicroscopy, e.g., using an inverted tissue culture microscope. Anabnormal cellular morphology can take the form of nuclear pleiomorphism.

As used herein, the term “selectively” means tending to occur at ahigher frequency in one population than in another population. Thecompared populations can be cell populations. Preferably, a compound ofthe present invention, or a pharmaceutically acceptable salt, prodrug,metabolite, polymorph or solvate thereof, acts selectively on a canceror precancerous cell but not on a normal cell. Preferably, a compound ofthe present invention, or a pharmaceutically acceptable salt, prodrug,metabolite, polymorph or solvate thereof, acts selectively to modulateone molecular target (e.g., a target kinase) but does not significantlymodulate another molecular target (e.g., a non-target kinase). Theinvention also provides a method for selectively inhibiting the activityof an enzyme, such as a kinase. Preferably, an event occurs selectivelyin population A relative to population B if it occurs greater than twotimes more frequently in population A as compared to population B. Anevent occurs selectively if it occurs greater than five times morefrequently in population A. An event occurs selectively if it occursgreater than ten times more frequently in population A; more preferably,greater than fifty times; even more preferably, greater than 100 times;and most preferably, greater than 1000 times more frequently inpopulation A as compared to population B. For example, cell death wouldbe said to occur selectively in cancer cells if it occurred greater thantwice as frequently in cancer cells as compared to normal cells.

A compound of the present invention, or a pharmaceutically acceptablesalt, prodrug, metabolite, polymorph or solvate thereof, can modulatethe activity of a molecular target (e.g., a target kinase). Modulatingrefers to stimulating or inhibiting an activity of a molecular target.Preferably, a compound of the present invention, or a pharmaceuticallyacceptable salt, prodrug, metabolite, polymorph or solvate thereof,modulates the activity of a molecular target if it stimulates orinhibits the activity of the molecular target by at least 2-foldrelative to the activity of the molecular target under the sameconditions but lacking only the presence of said compound. Morepreferably, a compound of the present invention, or a pharmaceuticallyacceptable salt, prodrug, metabolite, polymorph or solvate thereof,modulates the activity of a molecular target if it stimulates orinhibits the activity of the molecular target by at least 5-fold, atleast 10-fold, at least 20-fold, at least 50-fold, at least 100-foldrelative to the activity of the molecular target under the sameconditions but lacking only the presence of said compound. The activityof a molecular target may be measured by any reproducible means. Theactivity of a molecular target may be measured in vitro or in vivo. Forexample, the activity of a molecular target may be measured in vitro byan enzymatic activity assay or a DNA binding assay, or the activity of amolecular target may be measured in vivo by assaying for expression of areporter gene.

A compound of the present invention, or a pharmaceutically acceptablesalt, prodrug, metabolite, polymorph or solvate thereof, does notsignificantly modulate the activity of a molecular target if theaddition of the compound does not stimulate or inhibit the activity ofthe molecular target by greater than 10% relative to the activity of themolecular target under the same conditions but lacking only the presenceof said compound.

As used herein, the term “isozyme selective” means preferentialinhibition or stimulation of a first isoform of an enzyme in comparisonto a second isoform of an enzyme (e.g., preferential inhibition orstimulation of a kinase isozyme alpha in comparison to a kinase isozymebeta). Preferably, a compound of the present invention, or apharmaceutically acceptable salt, prodrug, metabolite, polymorph orsolvate thereof, demonstrates a minimum of a four fold differential,preferably a ten fold differential, more preferably a fifty folddifferential, in the dosage required to achieve a biological effect.Preferably, a compound of the present invention, or a pharmaceuticallyacceptable salt, prodrug, metabolite, polymorph or solvate thereof,demonstrates this differential across the range of inhibition, and thedifferential is exemplified at the IC₅₀, i.e., a 50% inhibition, for amolecular target of interest.

Administering a compound of the present invention, or a pharmaceuticallyacceptable salt, prodrug, metabolite, polymorph or solvate thereof, to acell or a subject in need thereof can result in modulation (i.e.,stimulation or inhibition) of an activity of a kinase of interest.

The present invention provides methods to assess biological activity ofa compound of the present invention, or a pharmaceutically acceptablesalt, prodrug, metabolite, polymorph or solvate thereof. In one method,an assay based on enzymatic activity can be utilized. In one specificenzymatic activity assay, the enzymatic activity is from a kinase. Asused herein, “kinase” refers to a large class of enzymes which catalyzethe transfer of the γ-phosphate from ATP to the hydroxyl group on theside chain of Ser/Thr or Tyr in proteins and peptides and are intimatelyinvolved in the control of various important cell functions, perhapsmost notably: signal transduction, differentiation, and proliferation.There are estimated to be about 2,000 distinct protein kinases in thehuman body, and although each of these phosphorylates particularprotein/peptide substrates, they all bind the same second substrate ATPin a highly conserved pocket. About 50% of the known oncogene productsare protein tyrosine kinases (PTKs), and their kinase activity has beenshown to lead to cell transformation. Preferably, the kinase assayed isa tyrosine kinase.

A change in enzymatic activity caused by a compound of the presentinvention, or a pharmaceutically acceptable salt, prodrug, metabolite,polymorph or solvate thereof, can be measured in the disclosed assays.The change in enzymatic activity can be characterized by the change inthe extent of phosphorylation of certain substrates. As used herein,“phosphorylation” refers to the addition of phosphate groups to asubstrate, including proteins and organic molecules; and, plays animportant role in regulating the biological activities of proteins.Preferably, the phosphorylation assayed and measured involves theaddition of phosphate groups to tyrosine residues. The substrate can bea peptide or protein.

In some assays, immunological reagents, e.g., antibodies and antigens,are employed. Fluorescence can be utilized in the measurement ofenzymatic activity in some assays. As used herein, “fluorescence” refersto a process through which a molecule emits a photon as a result ofabsorbing an incoming photon of higher energy by the same molecule.Specific methods for assessing the biological activity of the disclosedcompounds are described in the examples.

As used herein, an activity of c-Met refers to any biological functionor activity that is carried out by c-Met. For example, a function ofc-Met includes phosphorylation of downstream target proteins. Otherfunctions of c-Met include autophosphorylation, binding of adaptorproteins such as Gab-1, Grb-2, Shc, SHP2 and c-Cbl, and activation ofsignal transducers such as Ras, Src, PI3K, PLC-y, STATs, ERK1 and 2 andFAK.

Administering a compound of the present invention, or a pharmaceuticallyacceptable salt, prodrug, metabolite, polymorph or solvate thereof, to acell or a subject in need thereof results in modulation (i.e.,stimulation or inhibition) of an activity of an intracellular target(e.g., substrate). Several intracellular targets can be modulated withthe compounds of the present invention, including, but not limited to,adaptor proteins such as Gab-1, Grb-2, Shc, SHP2 and c-Cbl, and signaltransducers such as Ras, Src, PI3K, PLC-γ, STATs, ERK1 and 2 and FAK.

Activating refers to placing a composition of matter (e.g., protein ornucleic acid) in a state suitable for carrying out a desired biologicalfunction. A composition of matter capable of being activated also has anunactivated state. An activated composition of matter may have aninhibitory or stimulatory biological function, or both.

Elevation refers to an increase in a desired biological activity of acomposition of matter (e.g., a protein or a nucleic acid). Elevation mayoccur through an increase in concentration of a composition of matter.

As used herein, “a cell cycle checkpoint pathway” refers to abiochemical pathway that is involved in modulation of a cell cyclecheckpoint. A cell cycle checkpoint pathway may have stimulatory orinhibitory effects, or both, on one or more functions comprising a cellcycle checkpoint. A cell cycle checkpoint pathway is comprised of atleast two compositions of matter, preferably proteins, both of whichcontribute to modulation of a cell cycle checkpoint. A cell cyclecheckpoint pathway may be activated through an activation of one or moremembers of the cell cycle checkpoint pathway. Preferably, a cell cyclecheckpoint pathway is a biochemical signaling pathway.

As used herein, “cell cycle checkpoint regulator” refers to acomposition of matter that can function, at least in part, in modulationof a cell cycle checkpoint. A cell cycle checkpoint regulator may havestimulatory or inhibitory effects, or both, on one or more functionscomprising a cell cycle checkpoint. A cell cycle checkpoint regulatorcan be a protein or not a protein.

Treating cancer or a cell proliferative disorder can result in celldeath, and preferably, cell death results in a decrease of at least 10%in number of cells in a population. More preferably, cell death means adecrease of at least 20%; more preferably, a decrease of at least 30%;more preferably, a decrease of at least 40%; more preferably, a decreaseof at least 50%; most preferably, a decrease of at least 75%. Number ofcells in a population may be measured by any reproducible means. Anumber of cells in a population can be measured by fluorescenceactivated cell sorting (FACS), immunofluorescence microscopy and lightmicroscopy. Methods of measuring cell death are as shown in Li et al.,Proc Natl Acad Sci U S A. 100(5): 2674-8, 2003. In an aspect, cell deathoccurs by apoptosis.

Preferably, an effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph orsolvate thereof, is not significantly cytotoxic to normal cells. Atherapeutically effective amount of a compound is not significantlycytotoxic to normal cells if administration of the compound in atherapeutically effective amount does not induce cell death in greaterthan 10% of normal cells. A therapeutically effective amount of acompound does not significantly affect the viability of normal cells ifadministration of the compound in a therapeutically effective amountdoes not induce cell death in greater than 10% of normal cells. In anaspect, cell death occurs by apoptosis.

Contacting a cell with a compound of the present invention, or apharmaceutically acceptable salt, prodrug, metabolite, polymorph orsolvate thereof, can induce or activate cell death selectively in cancercells. Administering to a subject in need thereof a compound of thepresent invention, or a pharmaceutically acceptable salt, prodrug,metabolite, polymorph or solvate thereof, can induce or activate celldeath selectively in cancer cells. Contacting a cell with a compound ofthe present invention, or a pharmaceutically acceptable salt, prodrug,metabolite, polymorph or solvate thereof, can induce cell deathselectively in one or more cells affected by a cell proliferativedisorder. Preferably, administering to a subject in need thereof acompound of the present invention, or a pharmaceutically acceptablesalt, prodrug, metabolite, polymorph or solvate thereof, induces celldeath selectively in one or more cells affected by a cell proliferativedisorder.

The present invention relates to a method of treating or preventingcancer by administering a compound of the present invention, or apharmaceutically acceptable salt, prodrug, metabolite, polymorph orsolvate thereof, to a subject in need thereof, where administration ofthe compound of the present invention, or a pharmaceutically acceptablesalt, prodrug, metabolite, polymorph or solvate thereof, results in oneor more of the following: accumulation of cells in G1 and/or S phase ofthe cell cycle, cytotoxicity via cell death in cancer cells without asignificant amount of cell death in normal cells, antitumor activity inanimals with a therapeutic index of at least 2, and activation of a cellcycle checkpoint. As used herein, “therapeutic index” is the maximumtolerated dose divided by the efficacious dose.

One skilled in the art may refer to general reference texts for detaileddescriptions of known techniques discussed herein or equivalenttechniques. These texts include Ausubel et al., Current Protocols inMolecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al.,Molecular Cloning, A Laboratory Manual (3^(rd) edition), Cold SpringHarbor Press, Cold Spring Harbor, N.Y. (2000); Coligan et al., CurrentProtocols in Immunology, John Wiley & Sons, N.Y.; Enna et al., CurrentProtocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., ThePharmacological Basis of Therapeutics (1975), Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa., 18^(th) edition (1990).These texts can, of course, also be referred to in making or using anaspect of the invention

As used herein, “combination therapy” or “co-therapy” includes theadministration of a compound of the present invention, or apharmaceutically acceptable salt, prodrug, metabolite, polymorph orsolvate thereof, and at least a second agent as part of a specifictreatment regimen intended to provide the beneficial effect from theco-action of these therapeutic agents. The beneficial effect of thecombination includes, but is not limited to, pharmacokinetic orpharmacodynamic co-action resulting from the combination of therapeuticagents. Administration of these therapeutic agents in combinationtypically is carried out over a defined time period (usually minutes,hours, days or weeks depending upon the combination selected).“Combination therapy” may be, but generally is not, intended toencompass the administration of two or more of these therapeutic agentsas part of separate monotherapy regimens that incidentally andarbitrarily result in the combinations of the present invention.

“Combination therapy” is intended to embrace administration of thesetherapeutic agents in a sequential manner, wherein each therapeuticagent is administered at a different time, as well as administration ofthese therapeutic agents, or at least two of the therapeutic agents, ina substantially simultaneous manner. Substantially simultaneousadministration can be accomplished, for example, by administering to thesubject a single capsule having a fixed ratio of each therapeutic agentor in multiple, single capsules for each of the therapeutic agents.Sequential or substantially simultaneous administration of eachtherapeutic agent can be effected by any appropriate route including,but not limited to, oral routes, intravenous routes, intramuscularroutes, and direct absorption through mucous membrane tissues. Thetherapeutic agents can be administered by the same route or by differentroutes. For example, a first therapeutic agent of the combinationselected may be administered by intravenous injection while the othertherapeutic agents of the combination may be administered orally.Alternatively, for example, all therapeutic agents may be administeredorally or all therapeutic agents may be administered by intravenousinjection. The sequence in which the therapeutic agents are administeredis not narrowly critical.

“Combination therapy” also embraces the administration of thetherapeutic agents as described above in further combination with otherbiologically active ingredients and non-drug therapies (e.g., surgery orradiation treatment). Where the combination therapy further comprises anon-drug treatment, the non-drug treatment may be conducted at anysuitable time so long as a beneficial effect from the co-action of thecombination of the therapeutic agents and non-drug treatment isachieved. For example, in appropriate cases, the beneficial effect isstill achieved when the non-drug treatment is temporally removed fromthe administration of the therapeutic agents, perhaps by days or evenweeks.

A compound of the present invention, or a pharmaceutically acceptablesalt, prodrug, metabolite, analog or derivative thereof, may beadministered in combination with a second chemotherapeutic agent. Thesecond chemotherapeutic agent (also referred to as an anti-neoplasticagent or anti-proliferative agent) can be an alkylating agent; anantibiotic; an anti-metabolite; a detoxifying agent; an interferon; apolyclonal or monoclonal antibody, an EGFR inhibitor; a HER2 inhibitor,a histone deacetylase inhibitor, a hormone; a mitotic inhibitor, an MTORinhibitor, a multi-kinase inhibitor; a serine/threonine kinaseinhibitor; a tyrosine kinase inhibitors; a VEGF/VEGFR inhibitor; ataxane or taxane derivative, an aromatase inhibitor, an anthracycline, amicrotubule targeting drug, a topoisomerase poison drug, an inhibitor ofa molecular target or enzyme (e.g., a kinase inhibitor), a cytidineanalogue drug or any chemotherapeutic, anti-neoplastic oranti-proliferative agent listed inwww.cancer.org/docroot/cdg/cdg_(—)0.asp.

Exemplary alkylating agents include, but are not limited to,cyclophosphamide (Cytoxan; Neosar); chlorambucil (Leukeran); melphalan(Alkeran); carmustine (BiCNU); busulfan (Busulfex); lomustine (CeeNU);dacarbazine (DTIC-Dome); oxaliplatin (Eloxatin); carmustine (Gliadel);ifosfamide (Ifex); mechlorethamine (Mustargen); busulfan (Myleran);carboplatin (Paraplatin); cisplatin (CDDP; Platinol); temozolomide(Temodar); thiotepa (Thioplex); bendamustine (Treanda); or streptozocin(Zanosar).

Exemplary antibiotics include, but are not limited to, doxorubicin(Adriamycin); doxorubicin liposomal (Doxil); mitoxantrone (Novantrone);bleomycin (Blenoxane); daunorubicin (Cerubidine); daunorubicin liposomal(DaunoXome); dactinomycin (Cosmegen); epirubicin (Ellence); idarubicin(Idamycin); plicamycin (Mithracin); mitomycin (Mutamycin); pentostatin(Nipent); or valrubicin (Valstar).

Exemplary anti-metabolites include, but are not limited to, fluorouracil(Adrucil); capecitabine (Xeloda); hydroxyurea (Hydrea); mercaptopurine(Purinethol); pemetrexed (Alimta); fludarabine (Fludara); nelarabine(Arranon); cladribine (Cladribine Novaplus); clofarabine (Clolar);cytarabine (Cytosar-U); decitabine (Dacogen); cytarabine liposomal(DepoCyt); hydroxyurea (Droxia); pralatrexate (Folotyn); floxuridine(FUDR); gemcitabine (Gemzar); cladribine (Leustatin); fludarabine(Oforta); methotrexate (MTX; Rheumatrex); methotrexate (Trexall);thioguanine (Tabloid); TS-1 or cytarabine (Tarabine PFS).

Exemplary detoxifying agents include, but are not limited to, amifostine(Ethyol) or mesna (Mesnex).

Exemplary interferons include, but are not limited to, interferonalfa-2b (Intron A) or interferon alfa-2a (Roferon-A).

Exemplary polyclonal or monoclonal antibodies include, but are notlimited to, trastuzumab (Herceptin); ofatumumab (Arzerra); bevacizumab(Avastin); rituximab (Rituxan); cetuximab (Erbitux); panitumumab(Vectibix); tositumomab/iodine¹³¹ tositumomab (Bexxar); alemtuzumab(Campath); ibritumomab (Zevalin; In-111; Y-90 Zevalin); gemtuzumab(Mylotarg); eculizumab (Soliris) ordenosumab.

Exemplary EGFR inhibitors include, but are not limited to, gefitinib(Iressa); lapatinib (Tykerb); cetuximab (Erbitux); erlotinib (Tarceva);panitumumab (Vectibix); PKI-166; canertinib (CI-1033); matuzumab(Emd7200) or EKB-569.

Exemplary HER2 inhibitors include, but are not limited to, trastuzumab(Herceptin); lapatinib (Tykerb) or AC-480.

Histone Deacetylase Inhibitors include, but are not limited to,vorinostat (Zolinza).

Exemplary hormones include, but are not limited to, tamoxifen (Soltamox;Nolvadex); raloxifene (Evista); megestrol (Megace); leuprolide (Lupron;Lupron Depot; Eligard; Viadur); fulvestrant (Faslodex); letrozole(Femara); triptorelin (Trelstar LA; Trelstar Depot); exemestane(Aromasin); goserelin (Zoladex); bicalutamide (Casodex); anastrozole(Arimidex); fluoxymesterone (Androxy; Halotestin); medroxyprogesterone(Provera; Depo-Provera); estramustine (Emcyt); flutamide (Eulexin);toremifene (Fareston); degarelix (Firmagon); nilutamide (Nilandron);abarelix (Plenaxis); or testolactone (Teslac).

Exemplary mitotic inhibitors include, but are not limited to, paclitaxel(Taxol; Onxol; Abraxane); docetaxel (Taxotere); vincristine (Oncovin;Vincasar PFS); vinblastine (Velban); etoposide (Toposar; Etopophos;VePesid); teniposide (Vumon); ixabepilone (Ixempra); nocodazole;epothilone; vinorelbine (Navelbine); camptothecin (CPT); irinotecan(Camptosar); topotecan (Hycamtin); amsacrine or lamellarin D (LAM-D).

Exemplary MTOR inhibitors include, but are not limited to, everolimus(Afinitor) or temsirolimus (Torisel); rapamune, ridaforolimus; orAP23573.

Exemplary multi-kinase inhibitors include, but are not limited to,sorafenib (Nexavar); sunitinib (Sutent); BIBW 2992; E7080; Zd6474;PKC-412; motesanib; or AP24534.

Exemplary serine/threonine kinase inhibitors include, but are notlimited to, ruboxistaurin; eril/easudil hydrochloride; flavopiridol;seliciclib (CYC202; Roscovitrine); SNS-032 (BMS-387032); Pkc412;bryostatin; KAI-9803;SF1126; VX-680; Azd1152; Arry-142886 (AZD-6244);SCIO-469; GW681323; CC-401; CEP-1347 or PD 332991.

Exemplary tyrosine kinase inhibitors include, but are not limited to,erlotinib (Tarceva); gefitinib (Iressa); imatinib (Gleevec); sorafenib(Nexavar); sunitinib (Sutent); trastuzumab (Herceptin); bevacizumab(Avastin); rituximab (Rituxan); lapatinib (Tykerb); cetuximab (Erbitux);panitumumab (Vectibix); everolimus (Afinitor); alemtuzumab (Campath);gemtuzumab (Mylotarg); temsirolimus (Torisel); pazopanib (Votrient);dasatinib (Sprycel); nilotinib (Tasigna); vatalanib (Ptk787; ZK222584);CEP-701; SU5614; MLN518; XL999; VX-322; Azd0530; BMS-354825; SKI-606CP-690; AG-490; WHI-P154; WHI-P131; AC-220; or AMG888.

Exemplary VEGF/VEGFR inhibitors include, but are not limited to,bevacizumab (Avastin); sorafenib (Nexavar); sunitinib (Sutent);ranibizumab; pegaptanib; or vandetinib.

Exemplary microtubule targeting drugs include, but are not limited to,paclitaxel, docetaxel, vincristin, vinblastin, nocodazole, epothilonesand navelbine.

Exemplary topoisomerase poison drugs include, but are not limited to,teniposide, etoposide, adriamycin, camptothecin, daunorubicin,dactinomycin, mitoxantrone, amsacrine, epirubicin and idarubicin.

Exemplary taxanes or taxane derivatives include, but are not limited to,paclitaxel and docetaxol.

Exemplary general chemotherapeutic, anti-neoplastic, anti-proliferativeagents include, but are not limited to, altretamine (Hexylen);isotretinoin (Accutane; Amnesteem; Claravis; Sotret); tretinoin(Vesanoid); azacitidine (Vidaza); bortezomib (Velcade) asparaginase(Elspar); levamisole (Ergamisol); mitotane (Lysodren); procarbazine(Matulane); pegaspargase (Oncaspar); denileukin diftitox (Ontak);porfimer (Photofrin); aldesleukin (Proleukin); lenalidomide (Revlimid);bexarotene (Targretin); thalidomide (Thalomid); temsirolimus (Torisel);arsenic trioxide (Trisenox); verteporfin (Visudyne); mimosine(Leucenol); (1M tegafur-0.4 M 5-chloro-2,4-dihydroxypyrimidine-1 Mpotassium oxonate) or lovastatin.

In another aspect, the second chemotherapeutic agent can be a cytokinesuch as G-CSF (granulocyte colony stimulating factor). In anotheraspect, a compound of the present invention, or a pharmaceuticallyacceptable salt, prodrug, metabolite, analog or derivative thereof, maybe administered in combination with radiation therapy. Radiation therapycan also be administered in combination with a compound of the presentinvention and another chemotherapeutic agent described herein as part ofa multiple agent therapy. In yet another aspect, a compound of thepresent invention, or a pharmaceutically acceptable salt, prodrug,metabolite, analog or derivative thereof, may be administered incombination with standard chemotherapy combinations such as, but notrestricted to, CMF (cyclophosphamide, methotrexate and 5-fluorouracil),CAF (cyclophosphamide, adriamycin and 5-fluorouracil), AC (adriamycinand cyclophosphamide), FEC (5-fluorouracil, epirubicin, andcyclophosphamide), ACT or ATC (adriamycin, cyclophosphamide, andpaclitaxel), rituximab, Xeloda (capecitabine), Cisplatin (CDDP),Carboplatin, TS-1 (tegafur, gimestat and otastat potassium at a molarratio of 1:0.4:1), Camptothecin-11 (CPT-11, Irinotecan or Camptosar™) orCMFP (cyclophosphamide, methotrexate, 5-fluorouracil and prednisone).

In preferred embodiments, a compound of the present invention, or apharmaceutically acceptable salt, prodrug, metabolite, polymorph orsolvate thereof, may be administered with an inhibitor of an enzyme,such as a receptor or non-receptor kinase. Receptor and non-receptorkinases of the invention are, for example, tyrosine kinases orserine/threonine kinases. Kinase inhibitors of the invention are smallmolecules, polynucleic acids, polypeptides, or antibodies.

Exemplary kinase inhibitors include, but are not limited to, Bevacizumab(targets VEGF), BIBW 2992 (targets EGFR and Erb2), Cetuximab/Erbitux(targets Erb1), Imatinib/Gleevic (targets Bcr-Abl), Trastuzumab (targetsErb2), Gefitinib/Iressa (targets EGFR), Ranibizumab (targets VEGF),Pegaptanib (targets VEGF), Erlotinib/Tarceva (targets Erb1), Nilotinib(targets Bcr-Abl), Lapatinib (targets Erb1 and Erb2/Her2),GW-572016/lapatinib ditosylate (targets HER2/Erb2), Panitumumab/Vectibix(targets EGFR), Vandetinib (targets RET/VEGFR), E7080 (multiple targetsincluding RET and VEGFR), Herceptin (targets HER2/Erb2), PKI-166(targets EGFR), Canertinib/CI-1033 (targets EGFR),Sunitinib/SU-11464/Sutent (targets EGFR and FLT3), Matuzumab/Emd7200(targets EGFR), EKB-569 (targets EGFR), Zd6474 (targets EGFR and VEGFR),PKC-412 (targets VEGR and FLT3), Vatalanib/Ptk787/ZK222584 (targetsVEGR), CEP-701 (targets FLT3), SU5614 (targets FLT3), MLN518 (targetsFLT3), XL999 (targets FLT3), VX-322 (targets FLT3), Azd0530 (targetsSRC), BMS-354825 (targets SRC), SKI-606 (targets SRC), CP-690 (targetsJAK), AG-490 (targets JAK), WHI-P154 (targets JAK), WHI-P131 (targetsJAK), sorafenib/Nexavar (targets RAF kinase, VEGFR-1, VEGFR-2, VEGFR-3,PDGFR-β, KIT, FLT-3, and RET), Dasatinib/Sprycel (BCR/ABL and Src),AC-220 (targets Flt3), AC-480 (targets all HER proteins, “panHER”),Motesanib diphosphate (targets VEGF1-3, PDGFR, and c-kit), Denosumab(targets RANKL, inhibits SRC), AMG888 (targets HER3), and AP24534(multiple targets including Flt3).

Exemplary serine/threonine kinase inhibitors include, but are notlimited to, Rapamune (targets mTOR/FRAP1), Deforolimus (targets mTOR),Certican/Everolimus (targets mTOR/FRAP1), AP23573 (targets mTOR/FRAP1),Eril/Fasudil hydrochloride (targets RHO), Flavopiridol (targets CDK),Seliciclib/CYC202/Roscovitrine (targets CDK), SNS-032/BMS-387032(targets CDK), Ruboxistaurin (targets PKC), Pkc412 (targets PKC),Bryostatin (targets PKC), KAI-9803 (targets PKC), SF1126 (targets PI3K),VX-680 (targets Aurora kinase), Azd1152 (targets Aurora kinase),Arry-142886/AZD-6244 (targets MAP/MEK), SCIO-469 (targets MAP/MEK),GW681323 (targets MAP/MEK), CC-401 (targets JNK), CEP-1347 (targetsJNK), and PD 332991 (targets CDK).

4. Pharmaceutical Compositions

The present invention also provides pharmaceutical compositionscomprising a compound of formula I, Ia, Ib, II, IIa or IIb incombination with at least one pharmaceutically acceptable excipient orcarrier.

A “pharmaceutical composition” is a formulation containing the compoundsof the present invention in a form suitable for administration to asubject. In one embodiment, the pharmaceutical composition is in bulk orin unit dosage form. The unit dosage form is any of a variety of forms,including, for example, a capsule, an IV bag, a tablet, a single pump onan aerosol inhaler or a vial. The quantity of active ingredient (e.g., aformulation of the disclosed compound or salt, hydrate, solvate orisomer thereof) in a unit dose of composition is an effective amount andis varied according to the particular treatment involved. One skilled inthe art will appreciate that it is sometimes necessary to make routinevariations to the dosage depending on the age and condition of thepatient. The dosage will also depend on the route of administration. Avariety of routes are contemplated, including oral, pulmonary, rectal,parenteral, transdermal, subcutaneous, intravenous, intramuscular,intraperitoneal, inhalational, buccal, sublingual, intrapleural,intrathecal, intranasal, and the like. Dosage forms for the topical ortransdermal administration of a compound of this invention includepowders, sprays, ointments, pastes, creams, lotions, gels, solutions,patches and inhalants. In one embodiment, the active compound is mixedunder sterile conditions with a pharmaceutically acceptable carrier, andwith any preservatives, buffers or propellants that are required.

As used herein, the phrase “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, carriers, and/or dosage forms whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of human beings and animals without excessivetoxicity, irritation, allergic response, or other problem orcomplication, commensurate with a reasonable benefit/risk ratio.

“Pharmaceutically acceptable excipient” means an excipient that isuseful in preparing a pharmaceutical composition that is generally safe,non-toxic and neither biologically nor otherwise undesirable, andincludes excipient that is acceptable for veterinary use as well ashuman pharmaceutical use. A “pharmaceutically acceptable excipient” asused in the specification and claims includes both one and more than onesuch excipient.

A pharmaceutical composition of the invention is formulated to becompatible with its intended route of administration. Examples of routesof administration include parenteral, e.g., intravenous, intradermal,subcutaneous, oral (e.g., inhalation), transdermal (topical), andtransmucosal administration. Solutions or suspensions used forparenteral, intradermal, or subcutaneous application can include thefollowing components: a sterile diluent such as water for injection,saline solution, fixed oils, polyethylene glycols, glycerine, propyleneglycol or other synthetic solvents; antibacterial agents such as benzylalcohol or methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylenediaminetetraacetic acid;buffers such as acetates, citrates or phosphates, and agents for theadjustment of tonicity such as sodium chloride or dextrose. The pH canbe adjusted with acids or bases, such as hydrochloric acid or sodiumhydroxide. The parenteral preparation can be enclosed in ampoules,disposable syringes or multiple dose vials made of glass or plastic.

A compound or pharmaceutical composition of the invention can beadministered to a subject in many of the well-known methods currentlyused for chemotherapeutic treatment. For example, for treatment ofcancers, a compound of the invention may be injected directly intotumors, injected into the blood stream or body cavities or taken orallyor applied through the skin with patches. The dose chosen should besufficient to constitute effective treatment but not so high as to causeunacceptable side effects. The state of the disease condition (e.g.,cancer, precancer, and the like) and the health of the patient shouldpreferably be closely monitored during and for a reasonable period aftertreatment.

The term “therapeutically effective amount”, as used herein, refers toan amount of a pharmaceutical agent to treat, ameliorate, or prevent anidentified disease or condition, or to exhibit a detectable therapeuticor inhibitory effect. The effect can be detected by any assay methodknown in the art. The precise effective amount for a subject will dependupon the subject's body weight, size, and health; the nature and extentof the condition; and the therapeutic or combination of therapeuticsselected for administration. Therapeutically effective amounts for agiven situation can be determined by routine experimentation that iswithin the skill and judgment of the clinician. In a preferred aspect,the disease or condition to be treated is cancer. In another aspect, thedisease or condition to be treated is a cell proliferative disorder.

For any compound, the therapeutically effective amount can be estimatedinitially either in cell culture assays, e.g., of neoplastic cells, orin animal models, usually rats, mice, rabbits, dogs, or pigs. The animalmodel may also be used to determine the appropriate concentration rangeand route of administration. Such information can then be used todetermine useful doses and routes for administration in humans.Therapeutic/prophylactic efficacy and toxicity may be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., ED₅₀ (the dose therapeutically effective in 50% of thepopulation) and LD₅₀ (the dose lethal to 50% of the population). Thedose ratio between toxic and therapeutic effects is the therapeuticindex, and it can be expressed as the ratio, LD₅₀/ED₅₀. Pharmaceuticalcompositions that exhibit large therapeutic indices are preferred. Thedosage may vary within this range depending upon the dosage formemployed, sensitivity of the patient, and the route of administration.

Dosage and administration are adjusted to provide sufficient levels ofthe active agent(s) or to maintain the desired effect. Factors which maybe taken into account include the severity of the disease state, generalhealth of the subject, age, weight, and gender of the subject, diet,time and frequency of administration, drug combination(s), reactionsensitivities, and tolerance/response to therapy. Long-actingpharmaceutical compositions may be administered every 3 to 4 days, everyweek, or once every two weeks depending on half-life and clearance rateof the particular formulation.

The pharmaceutical compositions containing active compounds of thepresent invention may be manufactured in a manner that is generallyknown, e.g., by means of conventional mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping, orlyophilizing processes. Pharmaceutical compositions may be formulated ina conventional manner using one or more pharmaceutically acceptablecarriers comprising excipients and/or auxiliaries that facilitateprocessing of the active compounds into preparations that can be usedpharmaceutically. Of course, the appropriate formulation is dependentupon the route of administration chosen.

Pharmaceutical compositions suitable for injectable use include sterileaqueous solutions (where water soluble) or dispersions and sterilepowders for the extemporaneous preparation of sterile injectablesolutions or dispersion. For intravenous administration, suitablecarriers include physiological saline, bacteriostatic water, CremophorEL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In allcases, the composition must be sterile and should be fluid to the extentthat easy syringeability exists. It must be stable under the conditionsof manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol, andliquid polyethylene glycol, and the like), and suitable mixturesthereof. The proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.Prevention of the action of microorganisms can be achieved by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In manycases, it will be preferable to include isotonic agents, for example,sugars, polyalcohols such as manitol, sorbitol, sodium chloride in thecomposition. Prolonged absorption of the injectable compositions can bebrought about by including in the composition an agent which delaysabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the activecompound in the required amount in an appropriate solvent with one or acombination of ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the active compound into a sterile vehicle that contains abasic dispersion medium and the required other ingredients from thoseenumerated above. In the case of sterile powders for the preparation ofsterile injectable solutions, methods of preparation are vacuum dryingand freeze-drying that yields a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

Oral compositions generally include an inert diluent or an ediblepharmaceutically acceptable carrier. They can be enclosed in gelatincapsules or compressed into tablets. For the purpose of oral therapeuticadministration, the active compound can be incorporated with excipientsand used in the form of tablets, troches, or capsules. Oral compositionscan also be prepared using a fluid carrier for use as a mouthwash,wherein the compound in the fluid carrier is applied orally and swishedand expectorated or swallowed. Pharmaceutically compatible bindingagents, and/or adjuvant materials can be included as part of thecomposition. The tablets, pills, capsules, troches and the like cancontain any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate or Sterotes; a glidant such as colloidal silicondioxide; a sweetening agent such as sucrose or saccharin; or a flavoringagent such as peppermint, methyl salicylate, or orange flavoring.

For administration by inhalation, the compounds are delivered in theform of an aerosol spray from pressured container or dispenser, whichcontains a suitable propellant, e.g., a gas such as carbon dioxide, or anebulizer.

Systemic administration can also be by transmucosal or transdermalmeans. For transmucosal or transdermal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants are generally known in the art, and include, forexample, for transmucosal administration, detergents, bile salts, andfusidic acid derivatives. Transmucosal administration can beaccomplished through the use of nasal sprays or suppositories. Fortransdermal administration, the active compounds are formulated intoointments, salves, gels, or creams as generally known in the art.

The active compounds can be prepared with pharmaceutically acceptablecarriers that will protect the compound against rapid elimination fromthe body, such as a controlled release formulation, including implantsand microencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art. The materials can also be obtained commercially fromAlza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions(including liposomes targeted to infected cells with monoclonalantibodies to viral antigens) can also be used as pharmaceuticallyacceptable carriers. These can be prepared according to methods known tothose skilled in the art, for example, as described in U.S. Pat. No.4,522,811.

It is especially advantageous to formulate oral or parenteralcompositions in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form as used herein refers tophysically discrete units suited as unitary dosages for the subject tobe treated; each unit containing a predetermined quantity of activecompound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationfor the dosage unit forms of the invention are dictated by and directlydependent on the unique characteristics of the active compound and theparticular therapeutic effect to be achieved.

In therapeutic applications, the dosages of the pharmaceuticalcompositions used in accordance with the invention vary depending on theagent, the age, weight, and clinical condition of the recipient patient,and the experience and judgment of the clinician or practitioneradministering the therapy, among other factors affecting the selecteddosage. Generally, the dose should be sufficient to result in slowing,and preferably regressing, the growth of the tumors and also preferablycausing complete regression of the cancer. Dosages can range from about0.01 mg/kg per day to about 5000 mg/kg per day. In preferred aspects,dosages can range from about 1 mg/kg per day to about 1000 mg/kg perday. In an aspect, the dose will be in the range of about 0.1 mg/day toabout 50 g/day; about 0.1 mg/day to about 25 g/day; about 0.1 mg/day toabout 10 g/day; about 0.1 mg to about 3 g/day; or about 0.1 mg to about1 g/day, in single, divided, or continuous doses (which dose may beadjusted for the patient's weight in kg, body surface area in m², andage in years). An effective amount of a pharmaceutical agent is thatwhich provides an objectively identifiable improvement as noted by theclinician or other qualified observer. For example, regression of atumor in a patient may be measured with reference to the diameter of atumor. Decrease in the diameter of a tumor indicates regression.Regression is also indicated by failure of tumors to reoccur aftertreatment has stopped. As used herein, the term “dosage effectivemanner” refers to amount of an active compound to produce the desiredbiological effect in a subject or cell.

The pharmaceutical compositions can be included in a container, pack, ordispenser together with instructions for administration.

The compounds of the present invention are capable of further formingsalts. All of these forms are also contemplated within the scope of theclaimed invention.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the compounds of the present invention wherein the parent compound ismodified by making acid or base salts thereof. Examples ofpharmaceutically acceptable salts include, but are not limited to,mineral or organic acid salts of basic residues such as amines, alkalior organic salts of acidic residues such as carboxylic acids, and thelike. The pharmaceutically acceptable salts include the conventionalnon-toxic salts or the quaternary ammonium salts of the parent compoundformed, for example, from non-toxic inorganic or organic acids. Forexample, such conventional non-toxic salts include, but are not limitedto, those derived from inorganic and organic acids selected from2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethanedisulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic,glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic,hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic,isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic,mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic,pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic,salicyclic, stearic, subacetic, succinic, sulfamic, sulfanilic,sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurringamine acids, e.g., glycine, alanine, phenylalanine, arginine, etc.

Other examples of pharmaceutically acceptable salts include hexanoicacid, cyclopentane propionic acid, pyruvic acid, malonic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonicacid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid,camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylicacid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylaceticacid, muconic acid, and the like. The present invention also encompassessalts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, tromethamine,N-methylglucamine, and the like.

It should be understood that all references to pharmaceuticallyacceptable salts include solvent addition forms (solvates) or crystalforms (polymorphs) as defined herein, of the same salt.

The compounds of the present invention can also be prepared as esters,for example, pharmaceutically acceptable esters. For example, acarboxylic acid function group in a compound can be converted to itscorresponding ester, e.g., a methyl, ethyl or other ester. Also, analcohol group in a compound can be converted to its corresponding ester,e.g., an acetate, propionate or other ester.

The compounds of the present invention can also be prepared as prodrugs,for example, pharmaceutically acceptable prodrugs. The terms “pro-drug”and “prodrug” are used interchangeably herein and refer to any compoundwhich releases an active parent drug in vivo. Since prodrugs are knownto enhance numerous desirable qualities of pharmaceuticals (e.g.,solubility, bioavailability, manufacturing, etc.), the compounds of thepresent invention can be delivered in prodrug form. Thus, the presentinvention is intended to cover prodrugs of the presently claimedcompounds, methods of delivering the same and compositions containingthe same. “Prodrugs” are intended to include any covalently bondedcarriers that release an active parent drug of the present invention invivo when such prodrug is administered to a subject. Prodrugs in thepresent invention are prepared by modifying functional groups present inthe compound in such a way that the modifications are cleaved, either inroutine manipulation or in vivo, to the parent compound. Prodrugsinclude compounds of the present invention wherein a hydroxy, amino,sulfhydryl, carboxy or carbonyl group is bonded to any group that may becleaved in vivo to form a free hydroxyl, free amino, free sulfhydryl,free carboxy or free carbonyl group, respectively.

Examples of prodrugs include, but are not limited to, esters (e.g.,acetate, dialkylaminoacetates, formates, phosphates, sulfates andbenzoate derivatives) and carbamates (e.g., N,N-dimethylaminocarbonyl)of hydroxy functional groups, esters (e.g., ethyl esters,morpholinoethanol esters) of carboxyl functional groups, N-acylderivatives (e.g., N-acetyl) N-Mannich bases, Schiff bases andenaminones of amino functional groups, oximes, acetals, ketals and enolesters of ketone and aldehyde functional groups in compounds of theinvention, and the like, See Bundegaard, H., Design of Prodrugs, p1-92,Elesevier, New York-Oxford (1985).

The compounds, or pharmaceutically acceptable salts, esters or prodrugsthereof, are administered orally, nasally, transdermally, pulmonary,inhalationally, buccally, sublingually, intraperintoneally,subcutaneously, intramuscularly, intravenously, rectally,intrapleurally, intrathecally and parenterally. In one embodiment, thecompound is administered orally. One skilled in the art will recognizethe advantages of certain routes of administration.

The dosage regimen utilizing the compounds is selected in accordancewith a variety of factors including type, species, age, weight, sex andmedical condition of the patient; the severity of the condition to betreated; the route of administration; the renal and hepatic function ofthe patient; and the particular compound or salt thereof employed. Anordinarily skilled physician or veterinarian can readily determine andprescribe the effective amount of the drug required to prevent, counteror arrest the progress of the condition.

Techniques for formulation and administration of the disclosed compoundsof the invention can be found in Remington: the Science and Practice ofPharmacy, 19^(th) edition, Mack Publishing Co., Easton, Pa. (1995). Inan embodiment, the compounds described herein, and the pharmaceuticallyacceptable salts thereof, are used in pharmaceutical preparations incombination with a pharmaceutically acceptable carrier or diluent.Suitable pharmaceutically acceptable carriers include inert solidfillers or diluents and sterile aqueous or organic solutions. Thecompounds will be present in such pharmaceutical compositions in amountssufficient to provide the desired dosage amount in the range describedherein.

All percentages and ratios used herein, unless otherwise indicated, areby weight. Other features and advantages of the present invention areapparent from the different examples. The provided examples illustratedifferent components and methodology useful in practicing the presentinvention. The examples do not limit the claimed invention. Based on thepresent disclosure the skilled artisan can identify and employ othercomponents and methodology useful for practicing the present invention.

5. EXAMPLES Example 1 Synthesis of compound 1;4-(1-(3-methoxybenzyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-4(5H)-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amineStep 1.

A slurry of Sodium triacetoxyborohydride (0.25 M in anhydrousdichloroethane) (1 ml) was added to a mixture of 3-methoxy benzaldehyde(0.25 M in anhydrous dichloroethane) (480 μl) and tent-butyl2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carboxylate (0.25 M inanhydrous dichloroethane) (400 μl). The mixture was shaken at 50° C. for24-40 hours before 10% ammonia solution (1.5 ml) was added and sat atroom temperature for 1-2 hours, to allow for degassing. The vials wererecapped, vortexed and centrifuged. The dichloroethane layer was removedand the aqueous layer extracted with dichloroethane (2.5 ml). Thecombined dichloroethane fractions were evaporated to dryness to yieldtert-butyl1-(3-methoxybenzyl)-2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carboxylatewhich was used without further purification in steps 2 and 3.

Steps 2 and 3.

Step 2

tert-butyl1-(3-methoxybenzyl)-2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carboxylatewas dissolved in dichloroethane (1 ml) and 4M HCl in dioxane (500 μl)added. After being shaken at room temperature for 20 hours the mixturewas evaporated to dryness and the residue used directly in the nextstep.

Step 3

A 0.5 M solution of 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-amine indimethylsufoxide (800 μl, 4 eq.) was added to the product from theprevious step followed by diisopropylethylamine (1 ml). The mixture wasshaken at 120° C. for 24 hours before being evaporated to dryness. Theresidue obtained was dissolved in dimethylsulfoxide (1 ml) and purifiedby reverse phase chromatography on a preparative LC/UV/MS system using amass triggered fractionation. Compounds were eluted from the HPLC column(Maccel 120-10-C18 SH 10 μm 20 mmID×50 mm) at 88 ml/min with 5-95acetonitrile/water gradient using 0.1% TFA as modifier to afford4-(1-(3-methoxybenzyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-4(5H)-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine:LCMS m/e 402 (M+1).

Example 2 Synthesis of Compounds 2-47

Compounds 2-47 were prepared according to General Procedure 1 by usingan appropriate aldehyde in step 1 and either4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-amine or6-chloro-9H-purin-2-amine in step 3 in a similar manner to Example 1above.

Example 3 Synthesis of compound 48;6-(1-(2-chlorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-9H-purin-2-amineStep 1:

To a mixture of 2-chlorobenzaldehyde (0.5 M in dichloromethane) (800 μl)and 2-(3,4-dimethoxy-phenyl)-ethylamine (0.25 M in dichloromethane) (800μl) was added trifluoroacetic acid (150 μl). The mixture was shaken atroom temperature for 12-24 hours then evaporated to dryness. Toluene (1ml) was added the mixture vortexed and re-evaporated to dryness. Theresidue was dissolved in methanol (1.5 ml) and dichloromethane (1 ml)and filtered through a SCX cartridge (Bakerbond JT7090-07, aromaticsulfonic acid). The cartridge was washed with methanol (3 ml) theproduct eluted with 0.5 M ammonia solution (5 ml). Product containingfractions were combined and evaporated to dryness. Toluene (1 ml) wasadded the mixture vortexed and re-evaporated to dryness to give1-(2-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline whichwas used directly in the next step.

Step 2:

A solution of 6-chloro-9H-purin-2-amine (0.25 M in dimethylsulfoxide)(800+2400 DMSO or 3200 μl) was added to1-(2-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline followedby N,N-diisopropylethylamine (175 μl). The mixture was shaken at XX ° C.until complete then evaporated to dryness. The residue obtained wasshaken at 50° C. with ethyl acetate (3 ml) and water (2 ml), for 30minutes. The ethyl acetate layer was separated and the aqueous layerre-extracted with ethyl acetate (3 ml). The combined ethyl acetatefractions were evaporated to dryness and the residue obtained dissolvedin dimethylsulfoxide (1.5 ml).6-(1-(2-chlorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-9H-purin-2-aminewas purified from the dimethylsulfoxide solution by reverse phasechromatography on a preparative LC/UV/MS system using a mass triggeredfractionation. Compounds were eluted from the HPLC column (Maccel120-10-C18 SH 10 μm 20 mmID×50 mm) at 88 ml/min with 5-95acetonitrile/water gradient using 0.1% TFA as modifier: LCMS m/e 437(M+1).

Example 4 Synthesis of Compounds 49-51

Compounds 49-51 were prepared according to General Procedure 2 by usingan appropriate aldehyde in step 1 and either4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-amine or6-chloro-9H-purin-2-amine in step 2 in a similar manner to Example 3above.

Example 5 Tec Kinase Activity Assay

The disclosed compounds were assayed for their ability to inhibit theactivity of Tec kinase. Nunc Maxisorb plates were coated withstreptavidin by overnight incubation with 100 μL per well of 1 μg/mLStreptavidin in DPBS. Prior to the start of the experiment, the plateswere washed with TBST (3×200 μL) and blocked for at least 1 hour byadding 150 μL of 5% BSA/TBST. The plates were washed with TBST (3×200μL/well) and left dry immediately before the capture step.

The test articles and controls (Staurosporine and Sutent) were preparedusing the following assay buffer @ 3× desired final concentration (50 mMTris-HCl, 0.02 mg/mL BSA, 10 mM MgCl₂, 0.1 mM Na₃VO₄, 1 mM EGTA, 75 μMATP0.01% NP-40, 2 mM DTT in 10% glycerol/water). In a reaction platewere added rapidly 20 μL test article (or control) and 20 μL TEC 0.25ng/4. The plate was incubated for 30 minutes. To the reaction plate wasadded 20 μL of Pyk-2. 5 ng/μL. The plate was incubated at roomtemperature for two hours. From the reaction plate, 50 μL wastransferred to the streptavidin coated plate. The capture plate wasincubated at room temperature for 30 minutes then washed 6× with TBST.To the capture plate was added 100 μL/well of Cell Signalinganti-phospho tyrosine at a dilution of 1:3000 in 2% BSA/TBST. The platewas incubated for one hour at room temperature then washed 6× with TBST.To the capture plate was added 100 4/well of Alkaline Phosphatase TaggedGoat anti Mouse Antibody at a dilution of 1:4000 in 2% BSA/TBST. Theplate was incubated for one hour at room temperature then washed 6× withTBST. The fluorescent readout was initiated by the addition of 100μL/well of Attophos reagent (6 mg/10 mL). The reading was done on thePerkin Elmer Envision system.

Example 6 RET Kinase Activity Assay

The disclosed compounds were assayed for their ability to inhibit theactivity of RET kinase. Nunc Maxwasorb plates were coated withstreptavidin by overnight incubation with 100 μL per well of 1 μg/mLStreptavidin in DPBS. Prior to the start of the experiment, the plateswere washed with TBST (3×200 μL) and blocked for at least 1 hour byadding 150 μL of 5% BSA/TBST. The plates were washed with TBST (3×2004/well) and left dry immediately before the capture step.

The test articles and controls (Staurosporine and Sutent) were preparedusing the following assay buffer @ 3× desired final concentration (50 mMTrwas-HCl, 0.02 mg/mL BSA, 10 mM MgCl₂, 0.1 mM Na₃VO₄, 1 mM EGTA, 75 μMATP0.01% NP-40, 2 mM DTT in 10% glycerol/water). In a reaction plate,were added rapidly 20 μL test article (or control) and 20 μL RET (0.25ng/4 final concentration). The plate was incubated for 15 minutes. Tothe reaction plate was added 20 μL of Pyk-2 (0.25 ng/4 finalconcentration). The plate was incubated at room temperature for onehour.

From the reaction plate, 50 μL was transferred to the streptavidincoated plate. The capture plate was incubated at room temperature for 30minutes then washed 6× with TBST. To the capture plate was added 100μL/well of Cell Signaling anti-phospho tyrosine at a dilution of 1:3000in 2% BSA/TBST. The plate was incubated for one hour at room temperaturethen washed 6× with TBST. To the capture plate was added 100 4/well ofAlkaline Phosphatase Tagged Goat anti Mouse Antibody at a dilution of1:4000 in 2% BSA/TBST. The plate was incubated for one hour at roomtemperature then washed 6× with TBST. The fluorescent readout wasinitiated by the addition of 100 μL/well of Attophos reagent (6 mg/10mL). The reading was done on the Perkin Elmer Envision system.

Example 7 EphA8 Kinase Activity Assay

Nunc Maxisorb plates are coated with streptavidin by overnightincubation with 100 μL per well of 1 μg/ml Streptavidin in DPBS. Priorto the start of the experiment, the plates are washed with TBST (3×200μL) and blocked for at least 1 hour by adding 150 μL of 5% BSA/TBST. Theplates are washed with TBST (3×200 μL/well) and left dry immediatelybefore the capture step.

The test articles and control (Staurosporine) are prepared using thefollowing assay buffer @ 3× desired final concentration (50 mM Tris-HCl,0.02 mg/ml BSA, 10 mM MgCl₂, 0.1 mM Na₃VO₄, 1 mM EGTA, 12.5 μM ATP,0.01% NP-40, 1 mM DTT in 10% glycerol/water). In a reaction plate areadded rapidly 20 μl test article (or control) and 20 μl EphA8 (0.12ng/μl final concentration). The plate is incubated for 15 minutes. Tothe reaction plate is added 20 μl of Pyk-2 (0.75 ng/μl finalconcentration). The plate is incubated at room temperature for one hour.From the reaction plate, 50 μl is transferred to the streptavidin coatedplate. The capture plate is incubated at room temperature for 30minutes, then washed 6× with TBST. To the capture plate is added 1004/well of Cell Signaling anti-phospho tyrosine at a dilution of 1:3000in 2% BSA/TBST. The plate is incubated for one hour at room temperaturethen washed 6× with TBST. To the capture plate is added 100 4/well ofAlkaline Phosphatase Tagged Goat anti Mouse Antibody at a dilution of1:4000 in 2% BSA/TBST. The plate is incubated for one hour at roomtemperature then washed 6× with TBST. The fluorescent readout isinitiated by the addition of 100 μl/well of Attophos reagent (6 mg/10mL). The reading is done on the Perkin Elmer Envision system.

Table 4 shows the Tec, EphA8 and RET kinase inhibition activity ofrepresentative compounds of the invention. A=>79% inhibition, B=>50 to79% inhibition, C=<50% inhibition.

Example 8 MTS Cellular Assay

Cells were maintained at 37° C., 5% CO₂ in DMEM media supplemented with1% fetal bovine serum, penicillin/streptomycin and fungizone(Invitrogen). Cells were seeded into 96-well tissue culture plates at3000 per well and cultured at 37° C. for 18 hours. Test compounds weredissolved and diluted to 300× in DMSO then further diluted 1:40 in DMEMbefore addition to cells (1:7.5 dilution). Cells were incubated withtest compounds for 72 hours followed by incubation with tetrazoliumcompound(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium,inner salt; MTS) and the electron coupling reagent, phenazinemethosulfate (PMS) for 4 hours. MTS was chemically reduced bydehydrogenase in cells into formazan. The ability of compounds toinhibit cell growth in this assay is correlated with the reduction ofdehydrogenase enzyme activity found in metabolically active cells. Themeasurement of the absorbance of the formazan was assessed using anENVISION™ (Perkin Elmer) microplate reader at 492 nm. The calculatedIC₅₀ value is the concentration of the test compound that causes a 50%decrease in the absorbance. Compounds of the present invention inhibitthe growth of a variety of cancer cells. The data for certain compoundsof the invention are shown in Table 3. A=>79% inhibition, B=>50 to 79%inhibition, C=<50% inhibition.

TABLE 2 m/e Compound# IUPAC name (M + 1) 14-[1-(3-methoxybenzyl)-1,2,3,5- 402 tetrahydro-4H-1,4-benzodiazepin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6- amine 26-[1-(3-methoxybenzyl)-1,2,3,5- 402 tetrahydro-4H-1,4-benzodiazepin-4-yl]-9H-purin-2-amine 3 6-[1-(4-isopropylbenzyl)-1,2,3,5- 414tetrahydro-4H-1,4-benzodiazepin-4- yl]-9H-purin-2-amine 44-[1-(4-isopropylbenzyl)-1,2,3,5- 414 tetrahydro-4H-1,4-benzodiazepin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6- amine 56-[1-(3-fluorobenzyl)-1,2,3,5- 390 tetrahydro-4H-1,4-benzodiazepin-4-yl]-9H-purin-2-amine 6 4-[1-(3-fluorobenzyl)-1,2,3,5- 390tetrahydro-4H-1,4-benzodiazepin-4- yl]-1H-pyrazolo[3,4-d]pyrimidin-6-amine 7 6-{1-[3-(3-chlorophenyl)propyl]- 434 1,2,3,5-tetrahydro-4H-1,4-benzodiazepin-4-yl}-9H-purin-2- amine 8 4-{1-[3-(3-chlorophenyl)propyl]-434 1,2,3,5-tetrahydro-4H-1,4- benzodiazepin-4-yl}-1H-pyrazolo[3,4-d]pyrimidin-6-amine 9 6-[1-(2-methoxybenzyl)-1,2,3,5- 402tetrahydro-4H-1,4-benzodiazepin-4- yl]-9H-purin-2-amine 104-[1-(2-methoxybenzyl)-1,2,3,5- 402 tetrahydro-4H-1,4-benzodiazepin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6- amine 116-[1-(2-methylbenzyl)-1,2,3,5- 386 tetrahydro-4H-1,4-benzodiazepin-4-yl]-9H-purin-2-amine 12 4-[1-(2-methylbenzyl)-1,2,3,5- 386tetrahydro-4H-1,4-benzodiazepin-4- yl]-1H-pyrazolo[3,4-d]pyrimidin-6-amine 13 6-[1-(2-chlorobenzyl)-1,2,3,5- 406tetrahydro-4H-1,4-benzodiazepin-4- yl]-9H-purin-2-amine 144-[1-(2-chlorobenzyl)-1,2,3,5- 406 tetrahydro-4H-1,4-benzodiazepin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6- amine 156-[1-(4-fluorobenzyl)-1,2,3,5- 390 tetrahydro-4H-1,4-benzodiazepin-4-yl]-9H-purin-2-amine 16 4-[1-(4-fluorobenzyl)-1,2,3,5- 390tetrahydro-4H-1,4-benzodiazepin-4- yl]-1H-pyrazolo[3,4-d]pyrimidin-6-amine 17 6-[1-(1-naphthylmethyl)-1,2,3,5- 422tetrahydro-4H-1,4-benzodiazepin-4- yl]-9H-purin-2-amine 186-(1-benzyl-1,2,3,5-tetrahydro-4H- 3721,4-benzodiazepin-4-yl)-9H-purin-2- amine 194-(1-benzyl-1,2,3,5-tetrahydro-4H- 372 1,4-benzodiazepin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine 20 6-{1-[3-(trifluoromethyl)benzyl]-440 1,2,3,5-tetrahydro-4H-1,4- benzodiazepin-4-yl}-9H-purin-2- amine 214-{1-[3-(trifluoromethyl)benzyl]- 440 1,2,3,5-tetrahydro-4H-1,4-benzodiazepin-4-yl}-1H-pyrazolo[3,4- d]pyrimidin-6-amine 226-[1-(4-chlorobenzyl)-1,2,3,5- 406 tetrahydro-4H-1,4-benzodiazepin-4-yl]-9H-purin-2-amine 23 4-[1-(4-chlorobenzyl)-1,2,3,5- 406tetrahydro-4H-1,4-benzodiazepin-4- yl]-1H-pyrazolo[3,4-d]pyrimidin-6-amine 24 6-[1-(3-chlorobenzyl)-1,2,3,5- 406tetrahydro-4H-1,4-benzodiazepin-4- yl]-9H-purin-2-amine 254-[1-(3-chlorobenzyl)-1,2,3,5- 406 tetrahydro-4H-1,4-benzodiazepin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6- amine 266-[1-(4-methylbenzyl)-1,2,3,5- 386 tetrahydro-4H-1,4-benzodiazepin-4-yl]-9H-purin-2-amine 27 6-[1-(3,4-dimethoxybenzyl)-1,2,3,5- 432tetrahydro-4H-1,4-benzodiazepin-4- yl]-9H-purin-2-amine 284-[1-(3,4-dimethoxybenzyl)-1,2,3,5- 432tetrahydro-4H-1,4-benzodiazepin-4- yl]-1H-pyrazolo[3,4-d]pyrimidin-6-amine 29 6-[1-(4-tert-butylbenzyl)-1,2,3,5- 428tetrahydro-4H-1,4-benzodiazepin-4- yl]-9H-purin-2-amine 304-[1-(4-tert-butylbenzyl)-1,2,3,5- 428tetrahydro-4H-1,4-benzodiazepin-4- yl]-1H-pyrazolo[3,4-d]pyrimidin-6-amine 31 6-[1-(2,4-dichlorobenzyl)-1,2,3,5- 441tetrahydro-4H-1,4-benzodiazepin-4- yl]-9H-purin-2-amine 324-[1-(2,4-dichlorobenzyl)-1,2,3,5- 441tetrahydro-4H-1,4-benzodiazepin-4- yl]-1H-pyrazolo[3,4-d]pyrimidin-6-amine 33 6-[1-(3-methylbenzyl)-1,2,3,5- 386tetrahydro-4H-1,4-benzodiazepin-4- yl]-9H-purin-2-amine 344-[1-(3-methylbenzyl)-1,2,3,5- 386 tetrahydro-4H-1,4-benzodiazepin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6- amine 356-[1-(2,5-dimethoxybenzyl)-1,2,3,5- 432tetrahydro-4H-1,4-benzodiazepin-4- yl]-9H-purin-2-amine 364-[1-(2,5-dimethoxybenzyl)-1,2,3,5- 432tetrahydro-4H-1,4-benzodiazepin-4- yl]-1H-pyrazolo[3,4-d]pyrimidin-6-amine 37 6-[1-(2,4-difluorobenzyl)-1,2,3,5- 408tetrahydro-4H-1,4-benzodiazepin-4- yl]-9H-purin-2-amine 384-[1-(2,4-difluorobenzyl)-1,2,3,5- 408tetrahydro-4H-1,4-benzodiazepin-4- yl]-1H-pyrazolo[3,4-d]pyrimidin-6-amine 39 6-{1-[3-(3-fluorophenyl)propyl]- 418 1,2,3,5-tetrahydro-4H-1,4-benzodiazepin-4-yl}-9H-purin-2- amine 40 6-[1-(3-phenylpropyl)-1,2,3,5-400 tetrahydro-4H-1,4-benzodiazepin-4- yl]-9H-purin-2-amine 414-[1-(3-phenylpropyl)-1,2,3,5- 400 tetrahydro-4H-1,4-benzodiazepin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6- amine 426-[1-(3,4-dichlorobenzyl)-1,2,3,5- 441tetrahydro-4H-1,4-benzodiazepin-4- yl]-9H-purin-2-amine 434-[1-(3,4-dichlorobenzyl)-1,2,3,5- 441tetrahydro-4H-1,4-benzodiazepin-4- yl]-1H-pyrazolo[3,4-d]pyrimidin-6-amine 44 6-{1-[3-(4-methylphenyl)propyl]- 414 1,2,3,5-tetrahydro-4H-1,4-benzodiazepin-4-yl}-9H-purin-2- amine 454-{1-[3-(4-methylphenyl)propyl]- 414 1,2,3,5-tetrahydro-4H-1,4-benzodiazepin-4-yl}-1H-pyrazolo[3,4- d]pyrimidin-6-amine 466-[1-(3,4-difluorobenzyl)-1,2,3,5- 408tetrahydro-4H-1,4-benzodiazepin-4- yl]-9H-purin-2-amine 474-[1-(3,4-difluorobenzyl)-1,2,3,5- 408tetrahydro-4H-1,4-benzodiazepin-4- yl]-1H-pyrazolo[3,4-d]pyrimidin-6-amine 48 6-[1-(2-chlorophenyl)-6,7-dimethoxy- 4373,4-dihydroisoquinolin-2(1H)-yl]-9H- purin-2-amine 496-[1-(3-chloro-2-fluorophenyl)-6,7- 455dimethoxy-3,4-dihydroisoquinolin- 2(1H)-yl]-9H-purin-2-amine 506-{6,7-dimethoxy-1-[3- 471 (trifluoromethyl)phenyl]-3,4-dihydroisoquinolin-2(1H)-yl}-9H-purin- 2-amine 514-[6,7-dimethoxy-1-(2-phenylethyl)- 4313,4-dihydroisoquinolin-2(1H)-yl]-1H- pyrazolo[3,4-d]pyrimidin-6-amine

TABLE 3 Representative MTS Assay Data DLD-1, KATO III, MDA-MB-231,NCI-H1299, PACA-2, PC-3, Compound MTS 72 hours MTS 72 hours MTS 72 hoursMTS 72 hours MTS 72 hours MTS 72 hours No at 10 uM at 10 uM at 10 uM at10 uM at 10 uM at 10 uM 8 A C C B C C 14 A A A B C A 21 A A A C C A 23 AC B A C C 28 A A A A A A 29 C C C C C C 30 A C C B C C 32 A B C A C C 36A A A A A A 39 A A A A A A 43 A C C B C C

TABLE 4 Representative Biological Assay Data Compound EphA8, % INH, Ret,% INH, Tec % INH, # at 30 uM at 30 uM at 30 uM 1 B B A 2 C B B 3 C C C 4C C B 6 B B B 7 C C B 8 C C A 9 C B B 10 C C A 11 C B B 12 C C B 13 C CC 14 C C B 15 C B B 16 B C B 17 B B B 20 B C B 21 C C B 23 B C C 24 B BB 25 C C B 26 C B C 27 C C B 28 C C B 29 B C C 30 C B B 31 C C C 32 C CB 33 C B C 34 C C B 35 C C B 36 C C B 37 C B B 38 C C B 39 C B C 40 C BA 41 C C B 42 C C C 43 B B A 44 C C C 45 B B A 46 C B C 47 C B B 48 C C49 C C C 50 C C 51 C B C

1. A compound of formula I:

or a salt or ester thereof, wherein: one of Z₁ and Z₂ is CR₃ the otheris N; X₂ and X₄ are independently C(O) or CH₂; X₃ is CR_(a)R_(b); Y isunsubstituted or substituted C₁-C₆ alkyl linker or a bond; m is 0, 1, 2,3, 4; R₁ is unsubstituted or substituted C₅-C₁₀ aryl, unsubstituted orsubstituted heteroaryl comprising 1-4 heteroatoms selected from N, O andS, unsubstituted or substituted C₃-C₁₀ carbocycle, unsubstituted orsubstituted heterocycle comprising 1-4 heteroatoms selected from N, Oand S, C(O)R_(c) or S(O)₂R_(c); R₃ is H, halogen, unsubstituted orsubstituted C₁-C₈ alkyl, unsubstituted or substituted C₅-C₁₀ aryl,unsubstituted or substituted heteroaryl comprising 1-4 heteroatomsselected from N, O and S, unsubstituted or substituted C₃-C₁₀ carbocycleor unsubstituted or substituted heterocycle comprising 1-4 heteroatomsselected from N, O and S; each R₄ is independently hydroxyl, halogen,unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or substitutedC₁-C₆ alkoxyl, amino, unsubstituted or substituted C₁-C₆ alkylamino,unsubstituted or substituted di-(C₁-C₆)alkylamino, unsubstituted orsubstituted C₅-C₁₀ aryl, unsubstituted or substituted heteroarylcomprising 1-4 heteroatoms selected from N, O and S, unsubstituted orsubstituted C₃-C₁₀ carbocycle, unsubstituted or substituted heterocyclecomprising 1-4 heteroatoms selected from N, O and S or any two adjacentR₄'s, together with the atoms to which they are attached, form a 5- to7-member ring optionally comprising 1-4 optionally comprising 1-4heteroatoms selected from N, O and S; R_(a) and R_(b) are independentlyH, unsubstituted or substituted C₁-C₆ alkyl, unsubstituted orsubstituted C₅-C₁₀ aryl, unsubstituted or substituted heteroarylcomprising 1-4 heteroatoms selected from N, O and S, unsubstituted orsubstituted C₃-C₁₀ carbocycle, unsubstituted or substituted heterocyclecomprising 1-4 heteroatoms selected from N, O and S; and R_(c) is H,unsubstituted or substituted C₁-C₈ alkyl, unsubstituted or substitutedC₅-C₁₀ aryl, unsubstituted or substituted heteroaryl comprising 1-4heteroatoms selected from N, O and S, unsubstituted or substitutedC₃-C₁₀ carbocycle or unsubstituted or substituted heterocycle comprising1-4 heteroatoms selected from N, O and S.
 2. The compound of claim 1,wherein the compound is a compound of formula Ia:

or a salt or ester thereof, wherein, X₂ and X₄ are independently C(O) orCH₂; X₃ is CR_(a)R_(b); Y is unsubstituted or substituted C₁-C₆ alkyllinker or a bond; m is 0, 1, 2, 3, 4; R₁ is unsubstituted or substitutedC₅-C₁₀ aryl, unsubstituted or substituted heteroaryl comprising 1-4heteroatoms selected from N, O and S, unsubstituted or substitutedC₃-C₁₀ carbocycle, unsubstituted or substituted heterocycle comprising1-4 heteroatoms selected from N, O and S, C(O)R_(c) or S(O)₂R_(c); R₃ isH, halogen, unsubstituted or substituted C₁-C₈ alkyl, unsubstituted orsubstituted C₅-C₁₀ aryl, unsubstituted or substituted heteroarylcomprising 1-4 heteroatoms selected from N, O and S, unsubstituted orsubstituted C₃-C₁₀ carbocycle or unsubstituted or substitutedheterocycle comprising 1-4 heteroatoms selected from N, O and S; each R₄is independently hydroxyl, halogen, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₁-C₆ alkoxyl, amino, unsubstitutedor substituted C₁-C₆ alkylamino, unsubstituted or substituteddi-(C₁-C₆)alkylamino, unsubstituted or substituted C₅-C₁₀ aryl,unsubstituted or substituted heteroaryl comprising 1-4 heteroatomsselected from N, O and S, unsubstituted or substituted C₃-C₁₀carbocycle, unsubstituted or substituted heterocycle comprising 1-4heteroatoms selected from N, O and S or any two adjacent R₄'s, togetherwith the atoms to which they are attached, form a 5- to 7-member ringoptionally comprising 1-4 optionally comprising 1-4 heteroatoms selectedfrom N, O and S; R_(a) and R_(b) are independently H, unsubstituted orsubstituted C₁-C₆ alkyl, unsubstituted or substituted C₅-C₁₀ aryl,unsubstituted or substituted heteroaryl comprising 1-4 heteroatomsselected from N, O and S, unsubstituted or substituted C₃-C₁₀carbocycle, unsubstituted or substituted heterocycle comprising 1-4heteroatoms selected from N, O and S; and R_(c) is H, unsubstituted orsubstituted C₁-C₈ alkyl, unsubstituted or substituted C₅-C₁₀ aryl,unsubstituted or substituted heteroaryl comprising 1-4 heteroatomsselected from N, O and S, unsubstituted or substituted C₃-C₁₀ carbocycleor unsubstituted or substituted heterocycle comprising 1-4 heteroatomsselected from N, O and S.
 3. The compound of claim 2, wherein X₂ and X₄are each CH₂, X₃ is CR_(a)R_(b) where R_(a) and R_(b) are each H, and R₃is H.
 4. The compound of claim 2, wherein m is 0, Y is unsubstituted orsubstituted C₁-C₆ alkyl linker and R₁ is unsubstituted or substitutedC₅-C₁₀ aryl.
 5. The compound of claim 4, wherein R₁ is unsubstituted orsubstituted phenyl.
 6. The compound of claim 1, wherein the compound isa compound of formula Ib:

or a salt or ester thereof, wherein, X₂ and X₄ are independently C(O) orCH₂; X₃ is CR_(a)R_(b); Y is unsubstituted or substituted C₁-C₆ alkyllinker or a bond; m is 0, 1, 2, 3, 4; R₁ is unsubstituted or substitutedC₅-C₁₀ aryl, unsubstituted or substituted heteroaryl comprising 1-4heteroatoms selected from N, O and S, unsubstituted or substitutedC₃-C₁₀ carbocycle, unsubstituted or substituted heterocycle comprising1-4 heteroatoms selected from N, O and S, C(O)R_(c) or S(O)₂R_(c); eachR₄ is independently hydroxyl, halogen, unsubstituted or substitutedC₁-C₆ alkyl, unsubstituted or substituted C₁-C₆ alkoxyl, amino,unsubstituted or substituted C₁-C₆ alkylamino, unsubstituted orsubstituted di-(C₁-C₆)alkylamino, unsubstituted or substituted C₅-C₁₀aryl, unsubstituted or substituted heteroaryl comprising 1-4 heteroatomsselected from N, O and S, unsubstituted or substituted C₃-C₁₀carbocycle, unsubstituted or substituted heterocycle comprising 1-4heteroatoms selected from N, O and S or any two adjacent R₄'s, togetherwith the atoms to which they are attached, form a 5- to 7-member ringoptionally comprising 1-4 optionally comprising 1-4 heteroatoms selectedfrom N, O and S; R_(a) and R_(b) are independently H, unsubstituted orsubstituted C₁-C₆ alkyl, unsubstituted or substituted C₅-C₁₀ aryl,unsubstituted or substituted heteroaryl comprising 1-4 heteroatomsselected from N, O and S, unsubstituted or substituted C₃-C₁₀carbocycle, unsubstituted or substituted heterocycle comprising 1-4heteroatoms selected from N, O and S; and R_(c) is H, unsubstituted orsubstituted C₁-C₈ alkyl, unsubstituted or substituted C₅-C₁₀ aryl,unsubstituted or substituted heteroaryl comprising 1-4 heteroatomsselected from N, O and S, unsubstituted or substituted C₃-C₁₀ carbocycleor unsubstituted or substituted heterocycle comprising 1-4 heteroatomsselected from N, O and S.
 7. The compound of claim 6, wherein X₂ and X₄are each CH₂, X₃ is CR_(a)R_(b), and R_(a) and R_(b) are each H.
 8. Thecompound of claim 7, wherein m is 0, Y is unsubstituted or substitutedC₁-C₆ alkyl linker and R₁ is unsubstituted or substituted C₅-C₁₀ aryl.9. The compound of claim 8, wherein R₁ is unsubstituted or substitutedphenyl.
 10. The compound of claim 1, wherein said compound is selectedfrom the group consisting of:

and pharmaceutically acceptable salts thereof
 11. A compound of formulaII:

or a salt or ester thereof, wherein: one of Z₁ and Z₂ is CR₃ the otheris N; Z is —(CH₂)_(n)—, —CH₂—O—(CH₂)_(n)— or a bond; m is 0, 1, 2, 3, 4;n is 1, 2, 3, 4, 5, 6; R₃ is H, halogen, unsubstituted or substitutedC₁-C₈ alkyl, unsubstituted or substituted C₅-C₁₀ aryl, unsubstituted orsubstituted heteroaryl comprising 1-4 heteroatoms selected from N, O andS, unsubstituted or substituted C₃-C₁₀ carbocycle or unsubstituted orsubstituted heterocycle comprising 1-4 heteroatoms selected from N, Oand S; each R₄ is independently hydroxyl, halogen, unsubstituted orsubstituted C₁-C₆ alkyl, unsubstituted or substituted C₁-C₆ alkoxyl,amino, unsubstituted or substituted C₁-C₆ alkylamino, unsubstituted orsubstituted di-(C₁-C₆)alkylamino, unsubstituted or substituted C₅-C₁₀aryl, unsubstituted or substituted heteroaryl comprising 1-4 heteroatomsselected from N, O and S, unsubstituted or substituted C₃-C₁₀carbocycle, unsubstituted or substituted heterocycle comprising 1-4heteroatoms selected from N, O and S or any two adjacent R₄'s, togetherwith the atoms to which they are attached, form a 5- to 7-member ringoptionally comprising 1-4 optionally comprising 1-4 heteroatoms selectedfrom N, O and S; and R₅ is H, unsubstituted or substituted C₁-C₆ alkyl,unsubstituted or substituted C₅-C₁₀ aryl, unsubstituted or substitutedheteroaryl comprising 1-4 heteroatoms selected from N, O and S,unsubstituted or substituted C₃-C₁₀ carbocycle or unsubstituted orsubstituted heterocycle comprising 1-4 heteroatoms selected from N, Oand S.
 12. The compound of claim 11, wherein the compound is a compoundof formula IIa:

or a salt or ester thereof, wherein, Z is —(CH₂)_(n)—, —CH₂—O—(CH₂)_(n)—or a bond; m is 0, 1, 2, 3, 4; n is 1, 2, 3, 4, 5, 6; R₃ is H, halogen,unsubstituted or substituted C₁-C₈ alkyl, unsubstituted or substitutedC₅-C₁₀ aryl, unsubstituted or substituted heteroaryl comprising 1-4heteroatoms selected from N, O and S, unsubstituted or substitutedC₃-C₁₀ carbocycle or unsubstituted or substituted heterocycle comprising1-4 heteroatoms selected from N, O and S; each R₄ is independentlyhydroxyl, halogen, unsubstituted or substituted C₁-C₆ alkyl,unsubstituted or substituted C₁-C₆ alkoxyl, amino, unsubstituted orsubstituted C₁-C₆ alkylamino, unsubstituted or substituteddi-(C₁-C₆)alkylamino, unsubstituted or substituted C₅-C₁₀ aryl,unsubstituted or substituted heteroaryl comprising 1-4 heteroatomsselected from N, O and S, unsubstituted or substituted C₃-C₁₀carbocycle, unsubstituted or substituted heterocycle comprising 1-4heteroatoms selected from N, O and S or any two adjacent R₄'s, togetherwith the atoms to which they are attached, form a 5- to 7-member ringoptionally comprising 1-4 optionally comprising 1-4 heteroatoms selectedfrom N, O and S; and R₅ is H, unsubstituted or substituted C₁-C₆ alkyl,unsubstituted or substituted C₅-C₁₀ aryl, unsubstituted or substitutedheteroaryl comprising 1-4 heteroatoms selected from N, O and S,unsubstituted or substituted C₃-C₁₀ carbocycle or unsubstituted orsubstituted heterocycle comprising 1-4 heteroatoms selected from N, Oand S.
 13. The compound of claim 12, wherein R₃ is H, Z is —(CH₂)_(n)—or a bond, and R₅ is unsubstituted or substituted C₅-C₁₀ aryl.
 14. Thecompound of claim 11, wherein the compound is a compound of formula IIb:

or a salt or ester thereof, wherein, Z is —(CH₂)_(n)—, —CH₂—O—(CH₂)_(n)—or a bond; m is 0, 1, 2, 3, 4; n is 1, 2, 3, 4, 5, 6; each R₄ isindependently hydroxyl, halogen, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₁-C₆ alkoxyl, amino, unsubstitutedor substituted C₁-C₆ alkylamino, unsubstituted or substituteddi-(C₁-C₆)alkylamino, unsubstituted or substituted C₅-C₁₀ aryl,unsubstituted or substituted heteroaryl comprising 1-4 heteroatomsselected from N, O and S, unsubstituted or substituted C₃-C₁₀carbocycle, unsubstituted or substituted heterocycle comprising 1-4heteroatoms selected from N, O and S or any two adjacent R₄'s, togetherwith the atoms to which they are attached, form a 5- to 7-member ringoptionally comprising 1-4 optionally comprising 1-4 heteroatoms selectedfrom N, O and S; and R₅ is H, unsubstituted or substituted C₁-C₆ alkyl,unsubstituted or substituted C₅-C₁₀ aryl, unsubstituted or substitutedheteroaryl comprising 1-4 heteroatoms selected from N, O and S,unsubstituted or substituted C₃-C₁₀ carbocycle or unsubstituted orsubstituted heterocycle comprising 1-4 heteroatoms selected from N, Oand S.
 15. The compound of claim 14, wherein Z is —(CH₂)_(n)— or a bond,and R₅ is unsubstituted or substituted C₅-C₁₀ aryl.
 16. The compound ofclaim 11, wherein said compound is selected from the group consistingof:

and pharmaceutically acceptable salts thereof.
 17. A pharmaceuticalcomposition comprising a compound of claim 1 or 11 and one or morepharmaceutically acceptable carriers.
 18. A method of treating a cellproliferative disorder by administering to a subject in need thereof, atherapeutically effective amount of a compound of claim 1 or 11, or apharmaceutically acceptable salt, prodrug, metabolite, analog orderivative thereof, in combination with a pharmaceutically acceptablecarrier, such that the disorder is treated.
 19. A method of treatingcancer by administering to a subject in need thereof, a therapeuticallyeffective amount of a compound of claim 1 or 11, or a pharmaceuticallyacceptable salt, prodrug, metabolite, analog or derivative thereof, incombination with a pharmaceutically acceptable carrier, such that thecancer is treated.
 20. A method of selectively inducing cell death inprecancerous or cancerous cells by contacting a cell with an effectiveamount of a compound of claim 1 or 11, or a pharmaceutically acceptablesalt, prodrug, metabolite, analog or derivative thereof, in combinationwith a pharmaceutically acceptable carrier, such that contacting thecell results in selective induction of cell death in the precancerous orcancer cells.